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Insights into the ANKRD11 variants and short-stature phenotype through literature review and ClinVar database search

Orphanet Journal of Rare Diseases volume 19, Article number: 292 (2024) Cite this article

Abstract

Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators during numerous biological processes. Its pathogenic variants are strongly linked to the pathogenesis and progression of multisystem disorder known as KBG syndrome. With the widespread application of high-throughput DNA sequencing technologies in clinical medicine, numerous pathogenic variants in the ANKRD11 gene have been reported. Patients with KBG syndrome usually exhibit a broad phenotypic spectrum with a variable degree of severity, even if having identical variants. In addition to distinctive dental, craniofacial and neurodevelopmental abnormalities, patients often present with skeletal anomalies, particularly postnatal short stature. The relationship between ANKRD11 variants and short stature is not well-understood, with limited knowledge regarding its occurrence rate or underlying biological mechanism involved. This review aims to provide an updated analysis of the molecular spectrum associated with ANKRD11 variants, investigate the prevalence of the short stature among patients harboring these variants, evaluate the efficacy of recombinant human growth hormone in treating children with short stature and ANKRD11 variants, and explore the biological mechanisms underlying short stature from both scientific and clinical perspectives. Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene. Among the 245 KBGS patients with height data, approximately 50% displayed short stature. Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited. ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes. Our review offers crucial insights into the association between ANKRD11 variants and short stature and provides valuable guidance for precise clinical diagnosis and treatment of patients with KBG syndrome.

Background

The ANKRD11 gene (OMIM#611192) is mapped to human chromosome 16q24.3 and encodes an ankyrin repeat domain-containing protein 11 that belongs to a member of the ankyrin repeats-containing cofactor family (ANCO). It is relatively conserved across species and ubiquitously expressed in multiple organs and tissues, particularly in the brain and ovary [1, 2]. The ANKRD11 protein, consisting of 2,663 amino acid residues, structurally includes the ankyrin domain (ANK), transcriptional activation domain (AD), transcriptional repression domains (RD1 and RD2), and multiple putative nuclear localization signals (NLSs) [3]. The N-terminal ANK domain follows the canonical helix-loop-helix-β-hairpin/loop configuration and is comprised of five consecutive ankyrin repeat motifs. Each motif contains a 33-residue sequence and facilitates protein-protein interaction to coordinate subsequent transcriptional regulatory processes [4,5,6]. The ANKRD11 protein binds to the conserved N-terminal Per-Arnt-Sim (PAS) region of p160 coactivator via its ANK domain, concurrently, recruits histone deacetylases (HDACs) through its RD1 or RD2 domain. When p160 coactivator binds to the hydrophobic cleft within the C-terminal ligand-binding domain (LBD) of nuclear receptors (NRs) through its LXXLL motifs, the assembly of p160/ANKRD11/HDACs complex suppresses NRs-mediated ligand-dependent transactivation [7]. The ANKRD11 protein also interacts with the N-terminal 84 amino acids of ADA3 (alteration/deficiency in activation 3), which is an essential part of the p300/CBP [cAMP-response-element binding protein-binding protein]-associated factor (P/CAF) complex. This complex connects coactivators to histone acetylation and basal transcription machinery, resulting in the recruitment of the P/CAF complex and the specific regulation of ADA3 coactivator in a transcription factor-dependent manner [8]. Moreover, the ANKRD11 protein is capable of amplifying p53 activity through the enhancement of P/CAF-mediated acetylation [6]. Overall, the ANKRD11 protein, through its various functional domains, collectively facilitates the formation of a molecular bridge between coactivators or corepressors and histone deacetylases (HDACs) or histone acetyltransferases (HATs), thereby precisely regulating the transcription of target genes.

Initially, ANKRD11 has been recognized as a tumor suppressor gene in breast cancer due to its location within the chromosomal region 16q24.3, which is widely acknowledged for its frequent loss of heterozygosity (LOH) among patients suffering from breast cancer [9, 10]. Under normal physiological conditions, the estrogen receptor (ER)/amplified in breast cancer 1 (AIB1)/ANKRD11/HDACs or transcriptional enhanced associate domain (TEAD)/yes-associated protein (YAP)/AIB1/ANKRD11 complex functions to suppress the transcriptional activation of oncogenes in breast cancer [11, 12]. However, aberrant DNA methylation of three CpGs within a 19-base pair region of the ANKRD11 promoter leads to its down-regulation, thereby disrupting the assembly of the complex and consequently promoting breast tumorigenesis [13]. ANKRD11 haploinsufficiency was later identified in KBG syndrome (KBGS) patient-focused clinical and molecular studies, confirming the dominant pathogenic mechanism responsible for this condition (OMIM#148050). KBGS was initially reported by Herrmann and colleagues in 1975 and characterized by macrodontia of the upper central incisors, distinctive craniofacial findings, postnatal short stature, skeletal anomalies and, neurodevelopmental disorders, sometimes with seizures and electroencephalogram (EEG) abnormalities [14,15,16]. Patients harboring ANKRD11 pathogenic variants exhibit overlapping features between KBGS and Cornelia de Lange syndrome or Coffin-Siris-like syndrome, particularly neurological and skeletal anomalies [17, 18]. KBGS typically presents with a wide range of phenotypic manifestations, each varying in severity [19]. The biological function and cellular mechanism of ANKRD11 variants associated with the KBGS features have garnered significant interest and attention within the academic community. Previous study has established the pivotal role of the ANKRD11 gene in proliferation, neurogenesis and neuronal localization of cortical neural precursor cells by utilizing a Yoda mice model harboring a point mutation within the ANKRD11-HDAC interaction region, and the underlying mechanism was linked to alterations in the acetylation patterns of specific lysine residues (H3K9, H4K5, H4K8, H4K16) on the target genes regulated by ANKRD11 [20]. Further investigation has revealed that ANKRD11 regulates pyramidal neuron migration and dendritic differentiation of mouse cerebral cortex through the coordination of P/CAF to facilitate the acetylation of both p53 and Histone H3, which subsequently leads to the activation of brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (TrkB) signaling pathway [21]. Moreover, Roth and their colleagues developed a heterozygous neural crest-specific ANKRD11-mutant mice model, and revealed that multiple ossification centers in the middle facial bone of mice failed to expand or fuse properly, leading to a significant delay in bone maturation and a severe restriction in bone remodeling [22]. Recent research has uncovered that conditional knockout of the ANKRD11 gene within murine embryonic neural crest leads to severe congenital cardiac malformations and the underlying mechanism was linked to a reduction in Sema3C expression levels, coupled with diminished mTOR and BMP signaling within the cardiac neural crest cells of the outflow tract [23]. Based on the accumulating evidence from ongoing research into gene functions, the relationship between ANKRD11 pathogenic variants and the clinical features of KBGS is better understood than ever before. However, the role of ANKRD11 variants in inducing short stature has not received sufficient attention, particularly regarding its frequency of occurrence and the underlying biological mechanisms of action.

Materials and methods

We investigated publicly available online resources including published literature in Web of Science, PubMed, Google Scholar, and Wanfang database by searching keywords “KBGS”, “ANKRD11”, “Short stature” and “Intellectual disability” as well as genetic testing records in ClinVar database between July 2011 and March 2024. In this review, we included a total of 78 published papers that encompassed cohort studies, case series or single-case reports, and gathered 583 ANKRD11 variants, which were classified as pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG)-Association for Molecular Pathology (AMP) guideline (Supplemental material 1). Among these variants, 202 were reported in published papers and 381 were described in the ClinVar database. Certain large deletions or duplications of the ANKRD11 gene were not considered in this analysis, as the complexity of their impact on the amino acid sequence of the encoded protein posed challenges for interpretation. We have also excluded patients with 16q24.3 microdeletions, 16q24.3 microduplications and dual molecular diagnosis involving ANKRD11 and/or flanking genes, as the role of other genes in contributing to the height phenotype remains uncertain. Furthermore, hotspot variants within ANKRD11 were analyzed in 838 patients, comprising 457 derived from the literature and 381 derived from the ClinVar database (Supplemental material 2). ANKRD11 allele frequency below 1% in the general poulation was obtained from gnomAD (http://gnomad-sg.org/). 245 patients were reported to have height data, of which 112 had a height SDS. The differences in height SDS among patients with short stature carrying various ANKRD11 variants were further analyzed (Supplemental material 3). Data was described as mean ± SDS, and analyzed with one-way analysis of variance (ANOVA) followed by Tukey’s multiple comparisons test. A significant difference was considered when the p-value was less than 0.05.

Molecular spectrum of ANKRD11 variants

Since ANKRD11 was identified as the causal gene for KBGS in 2011, more than 340 KBGS patients have been reported worldwide [24]. Considering the variant data documented in the ClinVar database, it is projected that the number of patients with ANKRD11 variants exceeds 800. Despite the global prevalence of KBGS worldwide remaining unknown, its prevalence is underestimated due to a limited understanding of the disease phenotype and molecular underpinning. Consequently, establishing the spectrum of genetic variation in the ANKRD11 gene holds the promise of not only enhancing our understanding of disease’s pathogenesis but also enabling clinicians to render a precise molecular diagnosis for KBGS. A total of 583 ANKRD11 variants encompassed nearly the entire sequence of amino acids [1, 2, 15, 17,18,19, 25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96] (Fig. 1). All identified ANKRD11 variants were present in a heterozygous state, aligning with early embryonic lethality of Yoda mice observed in homozygotes, as demonstrated by Barbaric et al. [3]. This review encapsulates the up-to-date molecular landscape of ANKRD11 variants, nevertheless, in light of the continual discovery of patients with newly identified ANKRD11 variants, it needs to be supplemented and updated in time.

Fig. 1
figure 1

Molecular spectrum of ANKRD11 variants. A total of 583 ANRKD11 (likely) pathogenic variants were collected through literature review and ClinVar database. ANKRD11 variants were shown by frameshift, nonsense, missense, splice and inframe deletion, respectively. ANK: ankyrin repeat domain, RD1: repression domain 1, AD: activation domain, RD2: repression domain 2

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All ANKRD11 variants in the map were classified into five types: frameshift variants (340/583, 58.32%), nonsense variants (163/583, 27.96%), missense variants (54/583, 9.26%), splicing variants (21/583, 3.60%) and inframe deletion variants (5/583, 0.86%) (Fig. 2). Variants occurring in ANK, RD1, AD, RD2 and non-domain region accounted for 3.60%, 10.12%, 9.09%, 15.10% and 62.09% of the total variant pool, respectively (Fig. 2). Multiple putative NLSs within the interval between the RD1 and AD regions were categorized as part of the non-domain segment, primarily due to the absence of definitive and evidence-based localization data [3, 5, 15, 48]. Specific variants occurring within these NLSs may impair the nuclear targeting of the ANKRD11 protein. Notably, the most common variants were frameshift and nonsense variants, which give rise to prematurely truncated forms of the ANKRD11 protein. 62.96% (34/54) of ANKRD11 missense variants were found to cluster within C-terminal RD2 region. The majority of these missense variants, particularly those impacting arginine residues, were reported to impair protein stability or transcriptional activity, however, they did not produce an obvious impact on the protein’s subcellular localization [61, 66]. Additionally, alternative splicing events predominantly affected the C-terminal RD2 (13/21) and N-terminal region (8/21). It is not surprising that those affecting 5’ and 3’ splice sites are commonly implicated as the underlying cause of hereditary disorders [97]. Nonetheless, how these hypothesized splicing variants impact the encoded protein requires an in-depth examination of splicing patterns by cDNA analysis, and frequently involves a Mini-gene assay. Other types of ANKRD11 variants were relatively uncommon including p.Lys1347del, p.Thr2471_Gly2474del, p.Glu2524_Lys2525del, p.Q2350del, and p.R595_A2663delinsS. Interestingly, p.Lys1347del has been demonstrated to significantly disrupt the transcriptional activation of downstream p21 gene but did not influence the levels of ANKRD11 mRNA or protein [2, 15, 19, 61]. Theoretically, protein-truncating variants (PTVs) cause a more detrimental effect on protein function compared to the consequences of amino acid deletions (≥ 1) and single amino acid substitution [98, 99]. The impact of various types of genetic variants on the ANKRD11 protein function requires further investigation by a range of functional analyses.

Fig. 2
figure 2

The percentage of different types of ANKRD11 variants located in different functional domains. The pie chart indicates the percentage of variants within different domains. 10 X 10 dot plot represents the percentage of different variant types. The column shows the the proportion of five mutation types within different domains of ANKRD11. ANK: ankyrin repeat domain, RD1: repression domain 1, AD: activation domain, RD2: repression domain 2

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Hotspot variants of ANKRD11 protein

Mutation rates vary significantly along nucleotide sequences such that variants often concentrate at certain positions called hotspots [100]. DNA sequences prone to variation are highly dependent of gene sequence and structure as well as its chromosomal location, such as GC-rich region, microsatellites, meiotic recombination, nonallelic homologous recombination, centromeric rearrangements, telomeres and subtelomeric regions, replication timing and common fragile sites [101, 102]. Therefore, hotspot variants are indicative of the structural and functional properties of DNA sequence. Within the spectrum of ANKRD11 variants, over two dozen distinct variants have been identified in at least three patients. Beyond a few variants that have been vertically inherited within a single family, the majority of variants were discovered in multiple sporadic patients, underscoring the propensity for these genetic variants to arise independently in unrelated individuals. Four hotspot variants of ANKRD11 protein were observed including p.Glu461Glnfs*48, p.Lys635Glnfs*26, p.Glu800Asnfs*62 and p.Lys803Argfs*5 (Fig. 3A). These four variants are frameshift variants generated by c.1381_1384delGAAA, c.1903_1907delAAACA, c.2395_2398delAAAG and c.2408_2412delAAAAA, respectively. Two additional prevalent frameshift variants were traced back to analogous genomic alterations including p.Asn725Lysfs*23 and p.Thr462Lysfs*47 arising from c.2175_2178delCAAA and c.1385_1388delCAAA, respectively. The propensity for short deletions within AAA-type-containing sequences may be associated with polymerase slippage events induced by tandem repeats, a well-established mechanism for indels [100]. Nonetheless, it should be highlighted that CCC-type-containing sequences exhibit a heightened vulnerability to this form of genetic variation [103, 104]. RD2 domain located at the C-terminus of ANKRD11 seemed to be particularly vulnerable to a range of variant events in KBGS patients, with missense variants being notably prevalent (Fig. 3A). Conversely, the missense variants occuring in RD2 domain were relatively rare in general population (Fig. 3B). This was consistent with the results of in vitro cellular assays, which showed that missense variants occurring in the RD2 domain impaired the protein function of ANKRD11 [66]. Some frameshift and nonsense variants of ANKRD11 have been identified in general population, such as p.Glu2082Argfs*20, p.Ser2180Phefs*6, p.Glu1075* and p.Gln2507*, indicating a pattern of variable expressivity and incomplete penetrance associated with ANKRD11 variants [2]. Taken together, the presence of hotspot variants offers valuable insights into the inherent vulnerability of specific DNA sequence to abnormal DNA repair, replication, and modification or environmental exposures. These findings warrant in-depth exploration at the molecular level to unravel the underlying mechanisms and implications.

Fig. 3
figure 3

Frequency of ANKRD11 variants in a total of 838 KBGS patients (A) and ANKRD11 allele frequency in general population (B). ANKRD11 allele frequency below 1% in general poulation was obtained from gnomAD (http://gnomad-sg.org/). The abscissa represents the full-length amino acid sequence of ANKRD11, and the ordinate represents the frequency

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ANKRD11 variants and short stature in patients with KBGS

Frequency of occurrence of short stature in patients with ANKRD11 variants

Short stature is defined as height less than − 2 standard deviation (SD) or below the third percentile of corresponding mean height for age-, gender- and race-matched populations [105, 106]. As widely recognized, height is a highly heritable characteristic, and is classically influenced by hundreds of common variants pinpointed by genome-wide association studies (GWAS) [107, 108]. By comparison, the impact of rare and low-frequency monogenic variants on height is more pronounced, yielding a larger effect size compared to single nucleotide polymorphisms (SNPs) [109, 110]. Finding new genes with rare deleterious variants relating to growth is of considerable significance. Case series and individual reports serve as valuable sources of evidence for investigating the frequency of occurrence of short stature among patients harboring ANKRD11 variants. In 121 patients reported with height SDS, a significant proportion, amounting to 48.76% (59/121), exhibited a height below the − 2 SDS (Fig. 4A). This prevalence was observed with nearly equal frequency across genders, with female patients exhibiting a rate of 46.43% (26/56) and male patients exhibiting a rate of 49.02% (25/51). The height SDS of females and males were − 1.80 ± 1.27 and − 1.85 ± 1.28 SDS, respectively. Upon incorporating additional patients recorded with height percentile values into the analysis, the proportion of patients with short stature was found to be 47.35% (116/245). Moreover, while some patients did not exhibit short stature, their adult height SDS or growth percentile might be lower than expected if their genetic potential (mid-parental height) was taken into account. However, most studies did not report patients’ genetic potential for height, making it challenging to extract this specific information from the published literature. Overall, approximately half of the patients with ANKRD11 variants exhibited short stature, consequently, this characteristic stand as an important manifestation of KBGS attributable to ANKRD11 variants. Certainly, compared to other features, the incidence of short stature was less frequent than that of craniofacial anomalies (100%), dental anomalies (80%) and intellectual disability (77%) [48]. Notably, patients with ANKRD11 variants displayed a variable height phenotype ranging from as low as -4.9 SDS to as high as + 1.5 SDS. It can be ascribed to several factors, including genetic context of the gene, modified penetrance, variant type and variant location [111, 112]. There was no significant difference in height SDS among patients with ANKRD11 variants located in different regions or with different ANKRD11 variant types (p > 0.05) (Fig. 4B&C). Previous investigation has revealed that terminations close to the C-terminus of the ANKRD11 protein tended to have less severe short stature, but the research did not yield a statistically significant difference or a clear trend in the severity of short stature among the various types of ANKRD11 variants [39]. The findings of the current study indicated that no genotype-phenotype correlation was established. Certainly, a limited number of patients with ANKRD11 variants across different domains present a significant constraint on this conclusion.

Fig. 4
figure 4

Distribution of gender and height SDS of patients having ANKRD11 variants (A) and comparison of height SDS of patients having ANKRD11 variants within different domain (B) or having different ANKRD11 variant types (C). ANK: ankyrin repeat domain, RD1: repression domain 1, AD: activation domain, RD2: repression domain 2

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Frequency of ANKRD11 pathogenic variants in short-stature cohorts

Functional variants in the ANKRD11 gene have been identified through exome sequencing or gene panels in multiple short-stature cohorts (Table 1). The frequency of pathogenic variants was estimated to be between 0.35% and 0.55% [43, 68, 79, 113]. These variants were identified in patients initially diagnosed as having syndromic short stature, however, subsequent molecular diagnosis facilitated a more precise diagnosis of KBG syndrome. Syndromic short stature represents a phenotypic and genetically heterogeneous disease, and it accounts for a large part of the etiology of short stature. Considering the wide range of phenotypic manifestations and variable degree of severity, certain patients with short stature suffering from KBGS may not be accurately diagnosed in clinical practice. Consequently, it is likely that these patients harbor rare pathogenic variants in the ANKRD11 gene, which may elude detection and result in their classification within the vast and enigmatic group of short stature with undetermined etiologies. Genetic testing should be factored into precise diagnosis of syndromic short stature in the future. Based on previous studies estimating the occurrence of short stature at approximately 3% [114,115,116], the prevalence of ANKRD11 variants in the general population could be roughly calculated to be in the range of 0.0105–0.0165%. Nevertheless, given the limited sample sizes and the variability among different cohorts studied for short stature, the frequency of ANKRD11 variants remains uncertain and requires a more accurate assessment. This evaluation should ideally be conducted through large-scale population screenings, employing artificial intelligence-enhanced phenotyping in conjunction with genetic testing [117]. Despite the growing awareness and attention this condition has recently garnered in the clinical and genetic research communities, there remains a significant gap in the identification and management of KBGS patients. Therefore, the development of international consensus guidelines for the diagnosis of KBGS is of paramount importance.

Table 1 Frequency of ANKRD11 variants in multiple short-stature cohorts
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Recombinant human growth hormone therapy

In 1985, recombinant human growth hormone (rhGH) received approval from the US Food and Drug Administration (FDA) for the treatment of children with severe GHD. Since then, over the past nearly forty years, the application of rhGH has been progressively expanded to enhance the height outcomes in children with a variety of growth disorders, including chronic renal insufficiency (CRI), ISS, SGA without catch-up growth, Prader-Willi Syndrome (PWS), Noonan syndrome (NS), Turner syndrome (TS) and SHOX haploinsufficiency [118, 119]. The advent of high-throughput sequencing technology has ushered in a period of rapid advancement in the field of genetics and genomics, and this progress has significantly broadened our capacity for diagnosing and treating conditions associated with short stature. We are now entering a transformative era characterized by molecular diagnosis and the tailoring of therapeutic interventions to the specific genetic makeup of individuals, including their responsiveness to rhGH therapy [120]. It has been observed that pathogenic variants in the aggrecan (ACAN), natriuretic peptide receptor 2 (NPR2), and Indian hedgehog (IHH) genes, which are integral to growth plate development, have been consistently associated with a positive response to rhGH therapy [121,122,123,124,125]. In this review, we delineated the growth response observed in patients harboring ANKRD11 variants who received rhGH therapy (Table 2). The ages at initiation of rhGH treatment ranged from 5.2 to 14 years, and the treatment duration extended from 0.58 to 3 years. Following rhGH treatment, all patients exhibited varying levels of catch-up growth, as reflected by a range in Δ height SDS from 0.14 to 1.87. Among the nine patients, five showed a significant height improvement, reaching values above − 2 SDS ( -0.75 SDS for patient 3, − 0.7 SDS for patient 4, -1.86 SDS for patient 5, -1.8 SDS for patient 8 and − 1.91 SDS for patient 9). Most patients displayed either a good or moderate response to rhGH therapy. However, there was an exception with patient 3, a 7.9-year-old girl, whose height SDS only increased by 0.14 following a continuous treatment period of 0.58 years. Practically, a four-year-old girl form Australia with ANKRD11 variant (c.6472G > T, p.Glu2158*), showed no response to rhGH therapy [49]. The girl was not included in Table 2 due to the lack of height data. The potential existence of additional factors that may be contributing to the suboptimal response to rhGH remains uncertain.

Table 2 Height outcomes of patients having ANKRD11 variants and receiving growth hormone treatment
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Given the evidence suggesting that the ANKRD11 gene acts as a potential tumor suppressor due to its interaction with the p53 protein, particular attention should be paid to the safety profile of rhGH therapy, particularly oncogenic risks [126]. However, observational studies have reported no increased risk of mortality or the development of primary cancers among pediatric patients receiving rhGH treatment [127,128,129]. The implementation of cancer surveillance in patients clinically diagnosed as having KBGS due to ANKRD11 variants has been previously contemplated, and few patients were reported to develop malignant tumors [130, 131]. Short stature is one of all KBGS phenotypes that can be effectively treated with growth-promoting drugs, but there are few patients receiving rhGH treatment. The approval and accessibility of rhGH therapy for KBGS may be limited in certain countries, which highlights the imperative for further investigation and research within this specialized domain. In alignment with the recommendations proposed by Reynaert et al. [58], we advocate for a more favorable stance towards the implementation of short-term rhGH therapy for ANKRD11 variant-induced KBGS patients with severe short stature.

Underlying mechanisms of ANKRD11 variants causing short stature

Human longitudinal bone growth is persistently driven by the process of endochondral ossification within the epiphyseal growth plate that is characterized by three histologically distinct zones (resting, proliferative, and hypertrophic zones) throughout the stages of postnatal development [132]. As the slowly-cycling reserve cells, resting chondrocytes are maintained in a wingless-related integration site (Wnt)-inhibitory environment, and it contains a certain proportion of parathyroid hormone-related protein (PTHrP)-expressing skeletal stem-like cells producing rapidly proliferating columnar chondrocytes parallel to the direction of bone elongation [133]. Proliferative zone chondrocytes will differentiate into hypertrophic chondrocytes characterized by specific expression of type X collagen gene (Col10a1), and further undergo apoptosis or osteoblasts trans-differentiation, thereby contributing to bone elongation [134, 135]. The orchestrated differentiation of chondrocytes within the growth plate is governed by a complex interplay of numerous genes that are involved in a variety of signaling pathways, including hormonal signaling, paracrine signaling, intracellular pathways and extracellular matrix homeostasis (Fig. 5) [68, 136,137,138]. Functional variants in any of these genes can disrupt the growth plate chondrogenesis and impair the subsequent bone elongation. It was hypothesized that ANKRD11 plays a direct role in the transcriptional regulation of certain critical genes via intracellular pathways in the process of growth plate development [68]. In a prior investigation, Yoda mice with an N-ethyl-N-nitrosourea (ENU)-induced mutation in the ANKRD11 gene, exhibited a markedly reduced body size and presented with a phenotype reminiscent of osteoporosis compared to littermate controls [3]. However, no alterations were observed in the histological structure of the tibial growth plate and plasma IGF-1 level between six-month-old Yoda mice and wild-type mice. Given that growth plate in rodents do not undergo fusion but are instead subject to an age-related decrease following sexual maturation [139], it can be inferred that adult mice with ANKRD11 deficiency may not well accurately reflect the aberrant differentiation process of growth plate chondrocytes during rapid bone elongation. Data obtained from the International Mouse Phenotyping Consortium (IMPC) indicate that C57BL/6 N mice carrying a heterozygous ANKRD11tm1b(EUCOMM)Wtsi allele exhibited a reduction in body length when compared to their littermate controls (https://www.mousephenotype.org/data/genes/MGI:1924337). Additionally, mice with a conditional deletion of the ANKRD11 gene in neural crest cells dispalyed ossification centers that were either incapable of expansion or failed to fuse, demonstrating the critical regulatory role of ANKRD11 gene in intramembranous ossification [22]. In vitro studies further revealed that ANKRD11 was capable of enhancing the transactivation of the p21 gene, a key factor in the chondrogenic differentiation of ATDC5 cells induced by insulin supplements [61]. The chondrogenic differentiation of ATDC5 cells induced by insulin-transferrin-selenium is a widely recognized in vitro model mimicking endochondral ossification [140,141,142,143]. The potential role of the ANKRD11-p21 signaling pathway in growth plate development as a plausible mechanism to elucidate the short stature observed in KBGS patients warrants further investigation. To elucidate the functional mechanisms of the ANKRD11 gene in the physiological process of growth plate development, it is essential to conduct further study employing a mouse model with chondrocyte-specific ANKRD11 ablation, utilizing the CRISPR/Cas9 and Cre/LoxP recombination system.

Fig. 5
figure 5

Disease-causing genes associated with short stature through affecting the endochondral ossification of epiphyseal growth plate. The ANKRD11 gene may be implicated in this process as a transcription regulator. RZ: resting zone, PZ: proliferative zone, PHZ: prehypertrophic zone, HZ: hypertrophic zone

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Conclusions

Frameshift and nonsense were the most common types of ANKRD11 variants. Approximately half of the KBGS patients harboring ANKRD11 variants had short stature. However, the current study has not established a clear correlation between the genotype and this phenotypic manifestation. Some patients harboring ANKRD11 variants may initially be diagnosed as syndromic short stature due to limited recognition of KBGS. While patients with ANKRD11 variants exhibit a positive response to rhGH therapy, further investigation is warranted to substantiate its efficacy and safety. Functional variants in the ANKRD11 gene can potentially disrupt the longitudinal growth of bones by influencing the orderly differentiation process of growth plate chondrocytes, which needs deeper investigation through fundamental research to elucidate its underlying mechanisms.

Data availability

The original contributions presented in the study are included in the article/Supplementary Materials, further inquiries can be directed to the corresponding authors.

Abbreviations

ACAN:

Aggrecan

ACMG:

American college of medical genetics and genomics

AD:

Activation domain

ADA3:

Alteration/deficiency in activation 3

AIB1:

Amplified in breast cancer 1

AMP:

Association for molecular pathology

ANCO:

Ankyrin repeats-containing cofactor

ANK:

Ankyrin

ANKRD11:

Ankyrin repeat domain containing-protein 11

ANOVA:

One-way analysis of variance

BDNF:

Brain-derived neurotrophic factor

CAF:

[(CAMP-response-element binding protein)-binding protein]-associated factor

CBP:

(CAMP-response-element binding protein)-binding protein

CREB:

CAMP-response-element binding protein

CRI:

Chronic renal insufficiency

EEG:

Electroencephalogram

ENU:

N-ethyl-N-nitrosourea

ER:

Estrogen receptor

FDA:

Food and drug administration

GH:

Growth hormone

GHD:

Growth hormone deficiency

GHI:

Growth hormone insensitivity

GWAS:

Genome-wide association study

HAT:

Histone acetylase

HDAC:

Histone deacetylase

H3K9:

Histone 3 lysine 9

H4K5:

Histone 4 lysine 5

H4K8:

Histone 4 lysine 8

H4K16:

Histone 4 lysine 16

HtSDS:

Height standard deviation score

HZ:

Hypertrophic zone

IGF-1:

Insulin-like growth factor

IGFBP-3:

Insulin-like growth factor binding protein 3

IGHD:

Isolated growth hormone deficiency

IHH:

Indian hedgehog

IMPC:

International mouse phenotyping onsortium

Indel:

Insertion or deletion

IQ:

Intelligence quotient

ISS:

Idiopathic short stature

LBD:

Ligand-binding domain

MPHD:

Multiple pituitary hormone deficiency

MRI:

Magnetic resonance imaging

NLS:

Nuclear localization signal

NPR2:

Natriuretic peptide receptor 2

NRs:

Nuclear receptors

NS:

Noonan syndrome

OMIM:

Online mendelian inheritance in man

PAS:

Per-Arnt-Sim

PTHrP:

Parathyroid hormone-related protein

PTV:

Protein-truncating variant

PWS:

Prader-Willi syndrome

PZ:

Proliferative zone

RD:

Repression domain

rhGH:

Recombinant human growth hormone

RZ:

Resting zone

SD:

Standard deviation

SDS:

Standard deviation score

SGA:

Small for gestational age

SNP:

Single nucleotide polymorphism

SOC:

Secondary ossification center

TEAD:

Transcriptional enhanced associate domain

TrkB:

Tyrosine receptor kinase B

TS:

Turner syndrome

WES:

Whole exome sequencing

Wnt:

Wingless-related integration site

YAP:

Yes-associated protein

References

  1. Kang Y, He D, Li Y, Zhang Y, Shao Q, Zhang M, et al. A heterozygous point mutation of the ANKRD11 (c.2579C > T) in a Chinese patient with idiopathic short stature. Mol Genet Genomic Med. 2019;7(12):e988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Parenti I, Mallozzi MB, Huning I, Gervasini C, Kuechler A, Agolini E, et al. ANKRD11 variants: KBG syndrome and beyond. Clin Genet. 2021;100(2):187–200.

    Article  CAS  PubMed  Google Scholar 

  3. Barbaric I, Perry MJ, Dear TN, Rodrigues Da Costa A, Salopek D, Marusic A, et al. An ENU-induced mutation in the Ankrd11 gene results in an osteopenia-like phenotype in the mouse mutant Yoda. Physiol Genomics. 2008;32(3):311–21.

    Article  CAS  PubMed  Google Scholar 

  4. Mosavi LK, Cammett TJ, Desrosiers DC, Peng ZY. The ankyrin repeat as molecular architecture for protein recognition. Protein Sci. 2004;13(6):1435–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhang AH, Li CW, Chen JD. Characterization of transcriptional regulatory domains of ankyrin repeat cofactor-1. Biochem Bioph Res Co. 2007;358(4):1034–40.

    Article  CAS  Google Scholar 

  6. Neilsen PM, Cheney KM, Li CW, Chen JD, Cawrse JE, Schulz RB, et al. Identification of ANKRD11 as a p53 coactivator. J Cell Sci. 2008;121(21):3541–52.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang AH, Yeung PL, Li CW, Tsai SC, Dinh GK, Wu XY, et al. Identification of a novel family of ankyrin repeats containing cofactors for p160 nuclear receptor coactivators. J Biol Chem. 2004;279(32):33799–805.

    Article  CAS  PubMed  Google Scholar 

  8. Li CW, Dinh GK, Zhang AH, Chen JD. Ankyrin repeats-containing cofactors interact with ADA3 and modulate its co-activator function. Biochem J. 2008;413:349–57.

    Article  CAS  PubMed  Google Scholar 

  9. Whitmore SA, Crawford J, Apostolou S, Eyre H, Baker E, Lower KM, et al. Construction of a high-resolution physical and transcription map of chromosome 16q24.3: a region of frequent loss of heterozygosity in sporadic breast cancer. Genomics. 1998;50(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  10. Powell JA, Gardner AE, Bais AJ, Hinze SJ, Baker E, Whitmore S, et al. Sequencing, transcript identification, and quantitative gene expression profiling in the breast cancer loss of heterozygosity region 16q24.3 reveal three potential tumor-suppressor genes. Genomics. 2002;80(3):303–10.

    Article  CAS  PubMed  Google Scholar 

  11. Garee JP, Chien CD, Li JV, Wellstein A, Riegel AT. Regulation of HER2 oncogene transcription by a multifunctional coactivator/corepressor complex. Mol Endocrinol. 2014;28(6):846–59.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kushner MH, Ory V, Graham GT, Sharif GM, Kietzman WB, Thevissen S, et al. Loss of ANCO1 repression at AIB1/YAP targets drives breast cancer progression. Embo Rep. 2020;21(1):e48741.

    Article  CAS  PubMed  Google Scholar 

  13. Lim SP, Wong NC, Suetani RJ, Ho K, Ng JL, Neilsen PM, et al. Specific-site methylation of tumor suppressor ANKRD11 in breast cancer. Eur J Cancer. 2012;48(17):3300–9.

    Article  CAS  PubMed  Google Scholar 

  14. Herrmann J, Pallister PD, Tiddy W, Opitz JM. The KBG syndrome-a syndrome of short stature, characteristic facies, mental retardation, macrodontia and skeletal anomalies. Birth Defects Orig Artic Ser. 1975;11(5):7–18.

    CAS  PubMed  Google Scholar 

  15. Sirmaci A, Spiliopoulos M, Brancati F, Powell E, Duman D, Abrams A, et al. Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. Am J Hum Genet. 2011;89(2):289–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Morel Swols D, Foster IIJ, Tekin M. KBG syndrome. Orphanet J Rare Dis. 2017;12(1):183.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Cucco F, Sarogni P, Rossato S, Alpa M, Patimo A, Latorre A, et al. Pathogenic variants in EP300 and ANKRD11 in patients with phenotypes overlapping Cornelia De Lange syndrome. Am J Med Genet A. 2020;182(7):1690–6.

    Article  CAS  PubMed  Google Scholar 

  18. Miyatake S, Okamoto N, Stark Z, Nabetani M, Tsurusaki Y, Nakashima M, et al. ANKRD11 variants cause variable clinical features associated with KBG syndrome and coffin-siris-like syndrome. J Hum Genet. 2017;62(8):741–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Walz K, Cohen D, Neilsen PM, Foster IIJ, Brancati F, Demir K, et al. Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome. Hum Genet. 2015;134(2):181–90.

    Article  CAS  PubMed  Google Scholar 

  20. Gallagher D, Voronova A, Zander MA, Cancino GI, Bramall A, Krause MP, et al. Ankrd11 is a chromatin Regulator involved in Autism that is essential for neural development. Dev Cell. 2015;32(1):31–42.

    Article  CAS  PubMed  Google Scholar 

  21. Ka MH, Kim WY. ANKRD11 associated with intellectual disability and autism regulates dendrite differentiation via the BDNF/TrkB signaling pathway. Neurobiol Dis. 2018;111:138–52.

    Article  CAS  PubMed  Google Scholar 

  22. Roth DM, Baddam P, Lin HM, Vidal-Garcia M, Aponte JD, De Souza ST, et al. The chromatin regulator Ankrd11 controls palate and cranial bone development. Front Cell Dev Biol. 2021;9:645836.

    Article  Google Scholar 

  23. Yana K, Elia A, Ronan N, Adrianne W, Irina P, Nicole D, et al. The chromatin regulator Ankrd11 controls cardiac neural crest cell-mediated outflow tract remodeling and heart function. Nat Commun. 2024;15:4632.

  24. Elena MC, Fiona BK, Fermina LG, Saoud TS, Rosario LR, Rebeca LDP, Ignacio MF, Beatriz M, et al. Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients. J Med Genet. 2023;60:644–54.

    Article  Google Scholar 

  25. Xu MZ, Zhou HL, Yong J, Cong PK, Li CJ, Yu YS, et al. A Chinese patient with KBG syndrome and a 9q31.2-33.1 microdeletion. Eur J Med Genet. 2013;56(5):245–50.

    Article  PubMed  Google Scholar 

  26. Benson KA, White M, Allen NM, Byrne S, Carton R, Comerford E, et al. A comparison of genomic diagnostics in adults and children with epilepsy and comorbid intellectual disability. Eur J Hum Genet. 2020;28(8):1066–77.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chen J, Xia ZM, Zhou YL, Ma XM, Wang XD, Guo QW. A de novo frameshift variant of ANKRD11 (c.1366_1367dup) in a Chinese patient with KBG syndrome. BMC Med Genomics. 2021;14(1):68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kim HJ, Cho E, Park JB, Im WY, Kim HJ. A Korean family with KBG syndrome identified by ANKRD11 mutation, and phenotypic comparison of ANKRD11 mutation and 16q24.3 microdeletion. Eur J Med Genet. 2015;58(2):86–94.

    Article  PubMed  Google Scholar 

  29. Low K, Hills A, Williams M, Duff-Farrier C, McKee S, Smithson SF. A splice-site variant in ANKRD11 associated with classical KBG syndrome. Am J Med Genet A. 2017;173(10):2844–6.

    Article  CAS  PubMed  Google Scholar 

  30. Tanaka Y, Morisada N, Suzuki T, Ohashi Y, Ye MJ, Nozu K, et al. A woman with a dual genetic diagnosis of autosomal dominant tubulointerstitial kidney disease and KBG syndrome. CEN Case Rep. 2021;10(2):184–8.

    Article  PubMed  Google Scholar 

  31. de la Jimenez M, Fernandez-Mayoralas DM, Lopez-Martin S, Albert J, Calleja-Perez B, Fernandez-Perrone AL, et al. Abnormal frontal gyrification pattern and uncinate development in patients with KBG syndrome caused by ANKRD11 aberrations. Eur J Paediatr Neurol. 2021;35:8–15.

    Article  Google Scholar 

  32. Cianci P, Pezzoli L, Maitz S, Agosti M, Iascone M, Selicorni A. Dual genetic diagnoses: neurofibromatosis type 1 and KBG syndrome. Clin Dysmorphol. 2020;29(2):101–3.

    Article  PubMed  Google Scholar 

  33. Li Q, Yang L, Wu J, Lu W, Zhang M, Luo F. A case of KBG syndrome caused by mutation of ANKRD11 gene and literature review. Chin J Evid Based Pediatr. 2018;13(6):452–8.

    Google Scholar 

  34. Bianchi PM, Bianchi A, Digilio MC, Tucci FM, Sitzia E, De Vincentiis GC. Audiological findings in a de novo mutation of ANKRD11 gene in KBG syndrome: report of a case and review of the literature. Int J Pediatr Otorhinolaryngol. 2017;103:109–12.

    Article  PubMed  Google Scholar 

  35. Parenti I, Gervasini C, Pozojevic J, Graul-Neumann L, Azzollini J, Braunholz D, et al. Broadening of cohesinopathies: exome sequencing identifies mutations in ANKRD11 in two patients with Cornelia De Lange-overlapping phenotype. Clin Genet. 2016;89(1):74–81.

    Article  CAS  PubMed  Google Scholar 

  36. Wojciechowska K, Nurzynska-Flak J, Styka B, Kacprzak M, Lejman M. Case report: two newly diagnosed patients with KBG syndrome-two different molecular changes. Front Pediatr. 2021;9:649043.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Low K, Ashraf T, Canham N, Clayton-Smith J, Deshpande C, Donaldson A, et al. Clinical and genetic aspects of KBG syndrome. Am J Med Genet A. 2016;170(11):2835–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Goldenberg A, Riccardi F, Tessier A, Pfundt R, Busa T, Cacciagli P, et al. Clinical and molecular findings in 39 patients with KBG syndrome caused by deletion or mutation of ANKRD11. Am J Med Genet A. 2016;170(11):2847–59.

    Article  CAS  PubMed  Google Scholar 

  39. Li Q, Sun C, Yang L, Lu W, Luo F. Comprehensive analysis of clinical spectrum and genotype associations in Chinese and literature reported KBG syndrome. Transl Pediatr. 2021;10(4):834–42.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Aoi H, Mizuguchi T, Ceroni JR, Kim VEH, Furquim I, Honjo RS, et al. Comprehensive genetic analysis of 57 families with clinically suspected Cornelia De Lange syndrome. J Hum Genet. 2019;64(10):967–78.

    Article  CAS  PubMed  Google Scholar 

  41. Mattei D, Cavarzere P, Gaudino R, Antoniazzi F, Piacentini G. DYSMORPHIC features and adult short stature: possible clinical markers of KBG syndrome. Ital J Pediatr. 2021;47(1):15.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Ockeloen CW, Willemsen MH, de Munnik S, van Bon BWM, de Leeuw N, Verrips A, et al. Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations. Eur J Hum Genet. 2015;23(9):1176–85.

    Article  CAS  PubMed  Google Scholar 

  43. Homma TK, Freire BL, Kawahira RSH, Dauber A, Funari MFD, Lerario AM, et al. Genetic disorders in prenatal onset syndromic short stature identified by exome sequencing. J Pediatr. 2019;215:192–8.

    Article  CAS  PubMed  Google Scholar 

  44. Ansari M, Poke G, Ferry Q, Williamson K, Aldridge R, Meynert AM, et al. Genetic heterogeneity in Cornelia De Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism. J Med Genet. 2014;51(10):659–68.

    Article  CAS  PubMed  Google Scholar 

  45. Wong JKL, Campbell D, Ngo ND, Yeung F, Cheng G, Tang CSM, et al. Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes. BMC Med Genomics. 2016;9:75.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Ge XY, Ge L, Hu WW, Li XL, Hu YY. Growth hormone therapy for children with KBG syndrome: a case report and review of literature. World J Clin Cases. 2020;8(6):1172–9.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Alfieri P, Caciolo C, Lazzaro G, Menghini D, Cumbo F, Dentici ML, et al. Cognitive and adaptive characterization of children and adolescents with KBG syndrome: an explorative study. J Clin Med. 2021;10(7):1523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gao F, Zhao X, Cao B, Fan X, Li X, Li L, et al. Genetic and phenotypic spectrum of KBG syndrome: a report of 13 new Chinese cases and a review of the literature. J Pers Med. 2022;12(3):407.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Murray N, Burgess B, Hay R, Colley A, Rajagopalan S, McGaughran J, et al. KBG syndrome: an Australian experience. Am J Med Genet A. 2017;173(7):1866–77.

    Article  CAS  PubMed  Google Scholar 

  50. Gnazzo M, Lepri FR, Dentici ML, Capolino R, Pisaneschi E, Agolini E, et al. KBG syndrome: common and uncommon clinical features based on 31 new patients. Am J Med Genet A. 2020;182(5):1073–83.

    Article  PubMed  Google Scholar 

  51. Sayed ISM, Abdel-Hamid MS, Abdel-Salam GMH. KBG syndrome in two patients from Egypt. Am J Med Genet A. 2020;182(6):1309–12.

    Article  CAS  PubMed  Google Scholar 

  52. Kleyner R, Malcolmson J, Tegay D, Ward K, Maughan A, Maughan G, et al. KBG syndrome involving a single-nucleotide duplication in ANKRD11. Cold Spring Harb Mol Case Stud. 2016;2(6):a001131.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Libianto R, Wu KH, Devery S, Eisman JA, Center JR. KBG syndrome presenting with brachydactyly type E. Bone. 2019;123:18–22.

    Article  PubMed  Google Scholar 

  54. Alves RM, Uva P, Veiga MF, Oppo M, Zschaber FCR, Porcu G, et al. Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS + phenotypic spectrum: a case report. BMC Med Genet. 2019;20(1):16.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Scarano E, Tassone M, Graziano C, Gibertoni D, Tamburrino F, Perri A, et al. Novel mutations and unreported clinical features in KBG syndrome. Mol Syndromol. 2019;10(3):130–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Alfieri P, Demaria F, Licchelli S, Santonastaso O, Caciolo C, Digilio MC et al. Obsessive compulsive symptoms and psychopathological profile in children and adolescents with KBG syndrome. Brain Sci. 2019;9(11).

  57. De Bernardi ML, Ivanovski I, Caraffi SG, Maini I, Street ME, Bayat A, et al. Prominent and elongated coccyx, a new manifestation of KBG syndrome associated with novel mutation in ANKRD11. Am J Med Genet A. 2018;176(9):1991–5.

    Article  PubMed  Google Scholar 

  58. Reynaert N, Ockeloen CW, Savendahl L, Beckers D, Devriendt K, Kleefstra T, et al. Short stature in KBG syndrome: first responses to growth hormone treatment. Horm Res Paediatr. 2015;83(5):361–4.

    Article  CAS  PubMed  Google Scholar 

  59. Bayat A, Møller LB, Hjortshøj TD. Første Danske patient med et genkendeligt genetisk KBG-syndrom. Ugeskr Læger. 2018;180:V11170848.

    PubMed  Google Scholar 

  60. Latorre-Pellicer A, Ascaso Á, Lucia-Campos C, Gil-Salvador M, Arnedo M, Antoñanzas R, et al. Things are not always what they seem: from Cornelia De Lange to KBG phenotype in a girl with genetic variants in NIPBL and ANKRD11. Mol Genet Genomic Med. 2021;9(11):e1826.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Zhang TT, Yang Y, Yin XL, Wang XQ, Ni JH, Dong ZY, et al. Two loss-of-function ANKRD11 variants in Chinese patients with short stature and a possible molecular pathway. Am J Med Genet A. 2021;185(3):710–8.

    Article  CAS  PubMed  Google Scholar 

  62. Kim SJ, Yang A, Park JS, Kwon DG, Lee JS, Kwon YS, et al. Two novel mutations of ANKRD11 gene and wide clinical spectrum in KBG syndrome: case reports and literature review. Front Genet. 2020;11:579805.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Butler MG, Rafi SK, Hossain W, Stephan DA, Manzardo AM. Whole exome sequencing in females with autism implicates novel and candidate genes. Int J Mol Sci. 2015;16(1):1312–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Abe-Hatano C, Iida A, Kosugi S, Momozawa Y, Terao C, Ishikawa K, et al. Whole genome sequencing of 45 Japanese patients with intellectual disability. Am J Med Genet A. 2021;185(5):1468–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kutkowska-Kazmierczak A, Boczar M, Kalka E, Castaneda J, Klapecki J, Pietrzyk A, et al. Wide fontanels, delayed speech development and hoarse voice as useful signs in the diagnosis of KBG syndrome: a clinical description of 23 cases with pathogenic variants involving the ANKRD11 gene or submicroscopic chromosomal rearrangements of 16q24.3. Genes-Basel. 2021;12(8):1257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. de Boer E, Ockeloen CW, Kampen RA, Hampstead JE, Dingemans AJM, Rots D, et al. Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein. Genet Med. 2022;24(10):2051–64.

    Article  PubMed  Google Scholar 

  67. Hong JH, Kim SH, Lee ST, Choi JR, Kang HC, Lee JS, et al. Early diagnosis of KBG syndrome using diagnostic exome sequencing. J Korean Child Neurol Soc. 2018;26(4):272–75.

    Google Scholar 

  68. Li X, Yao R, Chang GY, Li Q, Song C, Li N, et al. Clinical profiles and genetic spectra of 814 Chinese children with short stature. J Clin Endocr Metab. 2022;107(4):972–85.

    Article  PubMed  Google Scholar 

  69. Nardello R, Mangano GD, Antona V, Fontana A, Striano P, Giorgio E, et al. Electroclinical features and outcome of ANKRD11-related KBG syndrome: a novel report and literature review. Seizure. 2021;85:151–4.

    Article  PubMed  Google Scholar 

  70. Samanta D, Willis E. Electroencephalographic findings in KBG syndrome: a child with novel mutation in ANKRD11 gene. Acta Neurol Belg. 2015;115(4):779–82.

    Article  PubMed  Google Scholar 

  71. Popp B, Ekici AB, Thiel CT, Hoyer J, Wiesener A, Kraus C, et al. Exome Pool-Seq in neurodevelopmental disorders. Eur J Hum Genet. 2017;25(12):1364–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Aitken S, Firth HV, McRae J, Halachev M, Kini U, Parker MJ, et al. Finding diagnostically useful patterns in quantitative phenotypic data. Am J Hum Genet. 2019;105(5):933–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Miao P, Feng JH, Guo YF, Wang JD, Xu XX, Wang Y, et al. Genotype and phenotype analysis using an epilepsy-associated gene panel in Chinese pediatric epilepsy patients. Clin Genet. 2018;94(6):512–20.

    Article  CAS  PubMed  Google Scholar 

  74. Meyer R, Soellner L, Begemann M, Dicks S, Fekete G, Rahner N, et al. Targeted next generation sequencing approach in patients referred for silver-Russell syndrome testing increases the mutation detection rate and provides decisive information for clinical management. J Pediatr. 2017;187:206–12.

    Article  CAS  PubMed  Google Scholar 

  75. Reuter MS, Chaturvedi RR, Liston E, Manshaei R, Aul RB, Bowdin S, et al. The cardiac genome clinic: implementing genome sequencing in pediatric heart disease. Genet Med. 2020;22(6):1015–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Cao YH, Zhang LY, Cao KF, Zhang GY. KBG syndrome: a case report and literature review. J Clin Pediatr. 2020;38(5):335–38.

    Google Scholar 

  77. Yang YY, Wen PQ, Su Z, Wang L, Zhao X. Gender difference in clinical manifestations of KBG syndrome due to variants of ANKRD11 gene. Chin J Med Genet. 2021;7:663–66.

    Google Scholar 

  78. Wang DY, Lai PJ, Li XB. Analysis of ANKRD11 gene variant in a family affected with KBG syndrome. Chin J Med Genet. 2020;37(9):1029–31.

    Google Scholar 

  79. Hauer NN, Popp B, Schoeller E, Schuhmann S, Heath KE, Hisado-Oliva A, et al. Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature. Genet Med. 2018;20(6):630–8.

    Article  CAS  PubMed  Google Scholar 

  80. Bestetti I, Crippa M, Sironi A, Tumiatti F, Masciadri M, Smeland MF, et al. Expanding the molecular spectrum of ANKRD11 gene defects in 33 patients with a clinical presentation of KBG syndrome. Int J Mol Sci. 2022;23(11):5912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wei SS, Li YY, Yang WL, Chen SX, Liu FP, Zhang M, et al. Functional investigation of a novel ANKRD11 frameshift variant identified in a Chinese family with KBG syndrome. Heliyon. 2024;10(6):e28082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Luca M, Elena C, Fjorilda C, Alice S, Roberto C, Sandra D, et al. A case of early-onset Parkinson’s disease in a patient with KBG syndrome. Neurol Sci. 2023;44:4537–39.

    Article  Google Scholar 

  83. Shangguan HK, Wang J, Lin JD, Huang XZ, Zeng Y, Chen RM. A study on genotypes and phenotypes of short stature caused by epigenetic modification gene variants. Eur J Pediatr. 2024;183(3):1403–14.

    Article  CAS  PubMed  Google Scholar 

  84. Zain A, Sanaa C, Cheryl C, Fowzan A, Stephen S, Sofia F, et al. ANKRD11 pathogenic variants and 16q24.3 microdeletions share an altered DNA methylation signature in patients with KBG syndrome. Hum Mol Genet. 2023;32(9):1429–38.

    Article  Google Scholar 

  85. Adelaide C, Camilla M, Ludovica P, Davide P, Fulvio DA, Veronica CB, et al. Cerebellar heterotopia: broadening the neuroradiological spectrum of KBG syndrome. Cerebellum. 2024;23:1736–40.

    Article  Google Scholar 

  86. Zhang HZ, Guo XN, Yang C, Zhang KH, Wang D, Wang J, et al. Clinical feature and genetic mutation of KBG syndrome diagnosed in neonatal period: a case report. Medicine. 2023;102(40):e35449.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Francesca P, Stefano GC, Gianluca C, Lara V, Manuela N, Giorgia C, et al. Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature. J Med Genet. 2023;60(12):1224–34.

    Article  Google Scholar 

  88. Ola K, Kathleen S, Drake C, Lily G, Elaine M, Anastassia V, et al. Documentation and prevalence of prenatal and neonatal outcomes in a cohort of individuals with KBG syndrome. Am J Med Genet A. 2023;191(9):2364–75.

    Article  Google Scholar 

  89. Robyn W, Madeline K, Sangeetha Y, Gregory C, Puneet J. Epilepsy in KBG Syndrome: report of additional cases. Pediatr Neurol. 2024;151:138–42.

    Article  Google Scholar 

  90. Auconi M, Serino D, Digilio MC, Gnazzo M, Conti M, Vigevano F, et al. Epilepsy in KBG syndrome. Dev Med Child Neurol. 2023;65(5):712–20.

    Article  PubMed  Google Scholar 

  91. Eoin PD, Kathleen MG, Amre S, Nicholas MA, et al. Epileptic dyskinetic encephalopathy in KBG syndrome: expansion of the phenotype. Epilepsy Behav Rep. 2024;25:100647.

    Article  Google Scholar 

  92. Anna A, Lior G, Shahar St, Gundula P, Ayan M, Zhong R, et al. Genetic insights into childhood-onset schizophrenia: the yield of clinical exome sequencing. Schizophr Res. 2023;252:138–45.

    Article  Google Scholar 

  93. Nada A, Siham CE, Maria Z, Amal C, Lamia A, Amal TI, et al. Identification of two novel ANKRD11 mutations: highlighting incomplete penetrance in KBG syndrome. Ann Lab Med. 2024;44(1):110–7.

    Article  Google Scholar 

  94. Choi YH, Choi JM, Do HS, Hwang SJ, Seo GH, Choi IH, et al. KBG syndrome: clinical features and molecular findings in seven unrelated Korean families with a review of the literature. Mol Genet Genomic Med. 2023;11(4):e2127.

    Article  PubMed  Google Scholar 

  95. Miyake N, Tsurusaki Y, Fukai R, Kushima I, Okamoto N, Ohashi K, et al. Molecular diagnosis of 405 individuals with autism spectrum disorder. Eur J Hum Genet. 2023. https://doi.org/10.1038/s41431-023-01335-7.

    Article  PubMed  Google Scholar 

  96. Wang L, Li J, Xu J, Xu Y, Wang J, Feng Y, et al. Clinical and genetic analysis of three children with KBG syndrome due to novel variants of ANKRD11 gene. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023;40(1):1–6.

    PubMed  Google Scholar 

  97. Caceres JF, Kornblihtt AR. Alternative splicing: multiple control mechanisms and involvement in human disease. Trends Genet. 2002;18(4):186–93.

    Article  CAS  PubMed  Google Scholar 

  98. Sevim Bayrak C, Stein D, Jain A, Chaudhary K, Nadkarni GN, Van Vleck TT, et al. Identification of discriminative gene-level and protein-level features associated with pathogenic gain-of-function and loss-of-function variants. Am J Hum Genet. 2021;108(12):2301–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Fu JM, Satterstrom FK, Peng MS, Brand H, Collins RL, Dong S, et al. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nat Genet. 2022;54(9):1320–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Rogozin IB, Pavlov YI. Theoretical analysis of mutation hotspots and their DNA sequence context specificity. Mutat Res-Rev Mutat. 2003;544(1):65–85.

    Article  CAS  Google Scholar 

  101. Nesta AV, Tafur D, Beck CR. Hotspots of human mutation. Trends Genet. 2021;37(8):717–29.

    Article  CAS  PubMed  Google Scholar 

  102. Seplyarskiy VB, Sunyaev S. The origin of human mutation in light of genomic data. Nat Rev Genet. 2021;22(10):672–86.

    Article  CAS  PubMed  Google Scholar 

  103. Taylor MS, Ponting CP, Copley RR. Occurrence and consequences of coding sequence insertions and deletions in mammalian genomes. Genome Res. 2004;14(4):555–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Montgomery SB, Goode DL, Kvikstad E, Albers CA, Zhang ZDD, Mu XJ, et al. The origin, evolution, and functional impact of short insertion-deletion variants identified in 179 human genomes. Genome Res. 2013;23(5):749–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Wang PP, Ji BL, Shao Q, Zhang M, Ban B. Association between insulin-like growth factor-1 and uric acid in Chinese children and adolescents with idiopathic short stature: a cross-sectional study. Biomed Res Int. 2018;2018:4259098.

    PubMed  PubMed Central  Google Scholar 

  106. Zhao Q, Zhang M, Chu Y, Sun H, Pan H, Ban B. A retrospective analysis of patients with short stature in Eastern China between 2013 and 2019. Biomed Res Int. 2021;2021:6640026.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Yang J, Benyamin B, McEvoy BP, Gordon S, Henders AK, Nyholt DR, et al. Common SNPs explain a large proportion of the heritability for human height. Nat Genet. 2010;42(7):565–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Durand C, Rappold GA. Height matters-from monogenic disorders to normal variation. Nat Rev Endocrinol. 2013;9(3):171–7.

    Article  CAS  PubMed  Google Scholar 

  109. Marouli E, Graff M, Medina-Gomez C, Lo KS, Wood AR, Kjaer TR, et al. Rare and low-frequency coding variants alter human adult height. Nature. 2017;542(7640):186–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Dauber A, Rosenfeld RG, Hirschhorn JN. Genetic evaluation of short stature. J Clin Endocrinol Metab. 2014;99(9):3080–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Vu V, Verster AJ, Schertzberg M, Chuluunbaatar T, Spensley M, Pajkic D, et al. Natural variation in gene expression modulates the severity of mutant phenotypes. Cell. 2015;162(2):391–402.

    Article  CAS  PubMed  Google Scholar 

  112. Castel SE, Cervera A, Mohammadi P, Aguet F, Reverter F, Wolman A, et al. Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk. Nat Genet. 2018;50(9):1327–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Fan X, Zhao S, Yu C, Wu D, Yan Z, Fan L, et al. Exome sequencing reveals genetic architecture in patients with isolated or syndromic short stature. J Genet Genomics. 2021;48(5):396–402.

    Article  CAS  PubMed  Google Scholar 

  114. Rappold GA, Fukami M, Niesler B, Schiller S, Z-umkeller W, Bettendorf M, et al. Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature. J Clin Endocrinol Metab. 2002;87(3):1402–6.

    Article  CAS  PubMed  Google Scholar 

  115. Argente J. Challenges in the management of short stature. Horm Res Paediatr. 2016;85(1):2–10.

    Article  CAS  PubMed  Google Scholar 

  116. Grunauer M, Jorge AAL. Genetic short stature. Growth Horm IGF Res. 2018;38:29–33.

    Article  PubMed  Google Scholar 

  117. Guo L, Park J, Yi E, Marchi E, Hsieh T, Kibalnyk Y et al. KBG syndrome: videoconferencing and use of artificial intelligence driven facial phenotyping in 25 new patients. Eur J Hum Genet. 2022;1–11.

  118. Ranke MB, Wit JM. Growth hormone-past, present and future. Nat Rev Endocrinol. 2018;14(5):285–300.

    Article  CAS  PubMed  Google Scholar 

  119. Collett-Solberg PF, Jorge AAL, Boguszewski MCS, Miller BS, Choong CSY, Cohen P, et al. Growth hormone therapy in children; research and practice-a review. Growth Horm Igf Res. 2019;44:20–32.

    Article  CAS  PubMed  Google Scholar 

  120. Dauber A. Genetic testing for the child with short stature-has the time come to change our diagnostic paradigm? J Clin Endocr Metab. 2019;104(7):2766–9.

    Article  PubMed  Google Scholar 

  121. Muthuvel G, Dauber A, Alexandrou E, Tyzinski L, Andrew M, Hwa V, et al. Treatment of short stature in aggrecan-deficient patients with recombinant human growth hormone: 1-year response. J Clin Endocr Metab. 2022;107(5):E2103–9.

    Article  PubMed  Google Scholar 

  122. van der Steen M, Pfundt R, Maas SJWH, Waarde WMBV, Odink RJ, Hokken-Koelega ACS. ACAN gene mutations in short children born SGA and response to growth hormone treatment. J Clin Endocr Metab. 2017;102(5):1458–67.

    Article  PubMed  Google Scholar 

  123. Ke XA, Liang HT, Miao H, Yang HB, Wang LJ, Gong FY, et al. Clinical characteristics of short-stature patients with an NPR2 mutation and the therapeutic response to rhGH. J Clin Endocr Metab. 2021;106(2):431–41.

    Article  PubMed  Google Scholar 

  124. Plachy L, Dusatkova P, Maratova K, Petruzelkova L, Zemkova D, Elblova L, et al. NPR2 variants are frequent among children with familiar short stature and respond well to growth hormone therapy. J Clin Endocr Metab. 2020;105(3):E746–52.

    Article  Google Scholar 

  125. Vasques GA, Funari MFA, Ferreira FM, Aza-Carmona M, Sentchordi-Montane L, Barraza-Garcia J, et al. IHH gene mutations causing short stature with nonspecific skeletal abnormalities and response to growth hormone therapy. J Clin Endocr Metab. 2018;103(2):604–14.

    Article  PubMed  Google Scholar 

  126. Noll JE, Jeffery J, Al-Ejeh F, Kumar R, Khanna KK, Callen DF, et al. Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11. Oncogene. 2012;31(23):2836–48.

    Article  CAS  PubMed  Google Scholar 

  127. Child CJ, Zimmermann AG, Chrousos GP, Cummings E, Deal CL, Hasegawa T, et al. Safety outcomes during pediatric GH therapy: final results from the prospective GeNeSIS observational program. J Clin Endocr Metab. 2019;104(2):379–89.

    Article  PubMed  Google Scholar 

  128. Child CJ, Zimmermann AG, Jia N, Robison LL, Bramswig JH, Blum WF. Assessment of primary cancer incidence in growth hormone-treated children: comparison of a multinational prospective observational study with population databases. Horm Res Paediat. 2016;85(3):198–206.

    Article  CAS  Google Scholar 

  129. Wilton P, Mattsson AF, Darendeliler F. Growth hormone treatment in children is not associated with an increase in the incidence of cancer: experience from KIGS (Pfizer International Growth Database). J Pediatr. 2010;157(2):265–70.

    Article  PubMed  Google Scholar 

  130. Behnert A, Auber B, Steinemann D, Frühwald MC, Huisinga C, Hussein K, et al. KBG syndrome patient due to 16q24. 3 microdeletion presenting with a paratesticular rhabdoid tumor: coincidence or cancer predisposition? Am J Med Genet A. 2018;176(6):1449–54.

    Article  CAS  PubMed  Google Scholar 

  131. Isrie M, Hendriks Y, Gielissen N, Sistermans EA, Willemsen MH, Peeters H, et al. Haploinsufficiency of ANKRD11 causes mild cognitive impairment, short stature and minor dysmorphisms. Eur J Hum Genet. 2012;20(2):131–3.

    Article  CAS  PubMed  Google Scholar 

  132. Lui JC. Home for a rest: stem cell niche of the postnatal growth plate. J Endocrinol. 2020;246(1):R1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Hallett SA, Matsushita Y, Ono W, Sakagami N, Mizuhashi K, Tokavanich N, et al. Chondrocytes in the resting zone of the growth plate are maintained in a wnt-inhibitory environment. Elife. 2021;10:e64513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Morris SA. Single-cell RNA-seq steps up to the growth plate. Trends Biotechnol. 2016;34(7):525–27.

    Article  CAS  PubMed  Google Scholar 

  135. Hallett SA, Ono W, Ono N. Growth plate chondrocytes: skeletal development, growth and beyond. Int J Mol Sci. 2019;20(23):6009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Wit JM, Oostdijk W, Losekoot M, van Duyvenvoorde HA, Ruivenkamp CA, Kant SG. MECHANISMS IN ENDOCRINOLOGY: novel genetic causes of short stature. Eur J Endocrinol. 2016;174(4):R145–73.

    Article  CAS  PubMed  Google Scholar 

  137. Baron J, Savendahl L, De Luca F, Dauber A, Phillip M, Wit JM, et al. Short and tall stature: a new paradigm emerges. Nat Rev Endocrinol. 2015;11(12):735–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Faienza MF, Chiarito M, Brunetti G, D’Amato G. Growth plate gene involment and isolated short stature. Endocrine. 2021;71(1):28–34.

    Article  CAS  PubMed  Google Scholar 

  139. Borjesson AE, Lagerquist MK, Windahl SH, Ohlsson C. The role of estrogen receptor alpha in the regulation of bone and growth plate cartilage. Cell Mol Life Sci. 2013;70(21):4023–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Negishi Y, Ui N, Nakajima M, Kawashima K, Maruyama K, Takizawa T, et al. p21Cip-1/SDI-1/WAF-1 gene is involved in chondrogenic differentiation of ATDC5 cells in vitro. J Biol Chem. 2001;276(35):33249–56.

    Article  CAS  PubMed  Google Scholar 

  141. Yao Y, Wang Y. ATDC5: an excellent in vitro model cell line for skeletal development. J Cell Biochem. 2013;114(6):1223–9.

    Article  CAS  PubMed  Google Scholar 

  142. Cheng X, Li P, Wang G, Yan Y, Li K. Microbiota-derived lipopolysaccharide retards chondrocyte hypertrophy in the growth plate through elevating Sox9 expression. J Cell Physiol. 2019;234(3):2593–605.

    Article  CAS  PubMed  Google Scholar 

  143. Dong X, Xu X, Yang C, Luo Y, Wu Y, Wang J. USP7 regulates the proliferation and differentiation of ATDC5 cells through the Sox9-PTHrP-PTH1R axis. Bone. 2021;143:115714.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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Funding

This work was supported by Research Fund for Academician Lin He New Medicine (JYHL2019FZD01) and the PhD Research Foundation of Affiliated Hospital of Jining Medical University (2018-BS-007), and was partly supported by Shandong Traditional Chinese Medicine Science and Technology Development Plans Project (2019 − 0486).

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  1. Department of Endocrinology, Genetics and Metabolism, Affiliated Hospital of Jining Medical University, Jining, Shandong, 272029, China

    Dongye He, Mei Zhang, Yanying Li, Fupeng Liu & Bo Ban

  2. Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, China

    Dongye He, Fupeng Liu & Bo Ban

  3. Chinese Research Center for Behavior Medicine in Growth and Development, Jining, China

    Mei Zhang, Yanying Li & Bo Ban

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  1. Dongye He
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Contributions

DYH performed the literature search and wrote the manuscript. MZ, YYL and FPL performed the literature search and collected ANKRD11 variants from ClinVar database. BB provided guidance on the data collection and critically revised the manuscript. All authors have reviewed and approved the final manuscript.

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Correspondence to Dongye He or Bo Ban.

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He, D., Zhang, M., Li, Y. et al. Insights into the ANKRD11 variants and short-stature phenotype through literature review and ClinVar database search. Orphanet J Rare Dis 19, 292 (2024). https://doi.org/10.1186/s13023-024-03301-y

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Orphanet Journal of Rare Diseases

ISSN: 1750-1172