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Table 1 Genetic testing strategies available for selected endocrine disorders. The disorders are listed according to the main thematic groups of the ENDO-ERN, but there is of course an overlap between them. As it can be deduced from the different examples, the decision about the genetic testing strategies (*) are mainly based on the spectrum of molecular variants and the clinical findings; In disorders, in which NGS-based multigene panel is the most efficient diagnostic testing procedure, this method listed in bold face. However, the listed procedures only represent examples and/or suggestions, but might differ between different laboratories. For further description of methods see Table 2. The four types of molecular changes (**) which can be detected by molecular testing are indicated for the different diseases, but it should be noted that the majority of variants are SNVs. Mode of inheritances (***) are divers, even within the same gene and disorder. In case of autosomal dominant (AD) inheritance de-novo occurrence is frequent

From: Genetic testing in inherited endocrine disorders: joint position paper of the European reference network on rare endocrine conditions (Endo-ERN)

Acronym Disorder Gene / Chromosomal Region OMIM Genetic testing strategy* Detection on different molecular levels (rates if available)** Differential diagnosis Mode of inheritance***
SNVs gene/exon targeted CNV analysis CNVs Epimut UPDs
Genetic adrenal disorders*
 ACC Adrenocortical carcinoma TP53 #202300 (1. sequencing of specific exons)
2. multigene panel
yes yes    ADCC can be observed in Beckwith-Wiedemann syndrome (see below) and is a component tumor in Li-Fraumeni syndrome. AD
 APS1 autoimmune polyendocrine syndrome type 1 AIRE #240300 1. single gene testing
2. multigene panel
yes yes    Overlap with several disorders. AR, AD
 CNC Carney complex PRKAR1A #160980 (type 1) 1. single gene testing
2. CNV analyses
3. multigene panel
60% 10%    Broad clinical spectrum and overlap with several disorders. It includes Cushing syndrome. AD
 PPNAD Primary pigmented nodular adrenocortical disease type 1 PRKAR1A #610489 AD
Primary pigmented nodular adrenocortical disease type 2 PDE11A #610475 yes   AD
Primary pigmented nodular adrenocortical disease type 3 PDE8B #614190 yes   AD
 21-OHD-CAH 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia CYP21A2 #201910 1. single gene testing. CNV analysis 70–80% 20–30%    Major type of CAH.  
Calcium and Phosphate Homeostasis*
 HRPT Hyperparathyroidism CDC73 #145000 Multigene panel yes yes     AD
Neonatal Hyperparathyroidism CASR #239200 yes    AD, AR
Familial Isolated Hypoparathyroidism GCM2 #146200 yes    AD, AR
hypocalciuric hypercalcaemia CASR
GNA11
AP2S21
#601198
#145981
#600740
yes    AD
 PHP / iPPSD Pseudohypoparathyroidism / Inactivated PTH/PTHrP Signalling Disorder GNAS #166350 #103580 #603233 #612462 #612463 Methylation-specific test single gene testing CNV analyses yes yes   yes Heterogeneous group of disorders caused by molecular changes of the imprinted GNAS locus. AD
 ADHR Autosomal dominant hypophosphatemic rickets FGF23 #193100 single gene testing yes yes     AD
 XLHR X-linked dominant hypophosaphatemic rickets PHEX #307800 single gene testing yes yes     X-linked
Genetic Pituitary Hormone Disorders*
 CPHD Combined Pituitary Hormone Deficiency PROP1 #262600 (1. single gene testing)
2. multigene panel
yes yes    The diagnosis of combined pituitary hormone deficiency (CPHD) requires the presence of growth hormone (GH) deficiency and deficiency of at least one other pituitary hormone. AR, AD
POU1F1 #613038
HESX1 #182230
others  
 FIPA Familial Isolated Pituitary Adenoma AIP #102200 single gene testing yes     Overlap with MEN1 AD,
somatic mosaicism
Genetic Thyroid Disorders*  
 HCNG Congenital non-goitrous hypothyroidism TSHR #275200 multigene panel yes yes    Molecularly heterogenous group of disorders. AD, AR
SLC5A5 #274400
PAX8 #218700
others  
Glucose and Insulin Homeostasis*
 MODY Maturity-Onset Diabetes of the Young type 1 HNF1A #600496 (1. single gene testing)
2. multigene panel
3. CNV analyses
yes yes    Currently 11 loci for MODY have been identified. 30–65% of patients carry mutations in HNF1A, 30–50% in GCK, 5–10% in HNF4A. AD
Maturity-Onset Diabetes of the Young type 2 GCK #125851
Maturity-Onset Diabetes of the Young type 1 HNF4A #125850
 TNDM Transient neonatal diabetes mellitus 6q24 (PLAG1) #601410 1. Methylation-specific test
2. single gene testing or multigene panel
no yes yes yes TNDM accounts for ~ 50% neonatal diabetes. Other genetic causes include pathogenic variants in KCNJ11 and ABCC8 (see PNDM). sporadic, AD, paternal inheritance; somatic mosaicism
KCNJ11 #610582 yes     AD
ABCC8 #610374     ;
 PNDM Permanent neonatal diabetes mellitus KCNJ11 #606176 multigene panel yes     KCNJ11 mutations account for 30% of patients, INS 20% and ABCC8 19%.J55 AD, AR
ABCC8
GCK
INS
PDX1
 HHF / CHI Familial hyperinsulinemic hypoglycemia / congenital hyperinsulinism ABCC8 #256450 (1. single gene testing)
2. multigene panel
yes yes   UPD as somatic event in focal type ABCC8 mutations account for 40–45% of patients. Focal type is due to a paternally inherited ABCC8 or KCNJ11 mutation plus somatic loss of heterozygosity (LOH). AD, AR
KCNJ11 #601820
others  
Genetic Endocrine Tumour Entities*
 MEN1 Multiple endocrine neoplasia type 1 MEN1 #131100 1. single gene testing
2. CNV detection
3. multigene panel
familial: 80–90% single: 65% 1–4%    multigene testing after MEN1 analysis: RET, CDKN1B, AIP, CASR, CDC73. AD
 MEN2 Multiple endocrine neoplasia type 2 RET #171400 1. testing for specific variants (C634R)
2. sequencing of whole gene
98 > 98%      AD
 MEN3 Multiple endocrine neoplasia type 3 #162300 1. testing for specific variants (M918T)
2. sequencing of whole gene
98 > 98% AD
 MEN4 Multiple endocrine neoplasia type 4 CDKN1B #620755 see MEN1 yes     see MEN1 AD
 VHL von Hippel-Lindau syndrome VHL #193300 1. single gene sequencing
2. CNV analyses
3. multigene panel
VHL: 89% VHL: 11%    broad clinical spectrum and overlap with several disorders. AD
 PPGL/PCC Hereditary Paranglioma- Pheochromocytomas MAX #171300 multigene panel; for specific phenotypes: sequencing of SDHB, SDHD dependent on the gene: up to 100% up to 15%    Broad clinical spectrum and overlap with several disorders. It includes Cushing syndrome. AD
SDHA #614165 AD
SDHAF2 #601650 AD
SDHB #115310 AD
SDHC #605373 AD
SDHD #168000 AD, paternal inheritance
TMEM127 #171300 AD
others     
Growth, Obesity and Metabolism*
 NS Noonan syndrome PTPN11 #163950 (1. sequencing of PTPN11)
2. multigene panel
nearly 100%     NS belongs to the group of RASopathies sharing affection of RAS pathway genes and overlapping features. AD, rarely AR
SOS1 #610733
RAF1 #611553
RIT1 #615355
others  
 BWS Beckwith-Wiedemann syndrome 11p15.5 #130650 1. methylation-specific test   < 1%   50% Broad clinical spectrum and overlap with several disorders. sporadic, rare cases: AD; somatic mosaicism
2. CDKN1C testing sporadic: 5% familial: 50%     AD, maternal inheritance
3. multigene panel single cases     AD, AR, X-linked
 SRS Silver-Russell syndrome 11p15.5 #180860 1. methylation-specific test     40% Broad clinical spectrum and overlap with several disorders sporadic, rare cases: AD; somatic mosaicism
2. Microarray    10%   AD
3. WES up to 10%     AD, AR, X-linked
7 methylation-specific test     10% som. Mosaic
14q32 methylation-specific test     10% som. Mosaic
 PWS Prader-Willi syncdrome 15q11.2 #176270 CNV analyses   75%    Clinical overlap with several disorders sporadic; rare cases: AD
methylation-specific test (also detects 15q11.2 CNVs)   75–80%   20–25%
 IGHD Isolated growth hormone deficiency type 1A GH1 #262400 single gene sequencing yes     Overlap with disorders caused by mutations in other members of the GH axis. AR
Isolated growth hormone deficiency type 1B GH1 #612781 AR
Isolated growth hormone deficiency type 2 GH1 #173100 AD
Isolated growth hormone deficiency type 4 GHRHR #618157 single gene sequencing yes     AD
 LS Laron dwarfism GHR #262500 single gene sequencing yes     AR
GHIP partial growth hormone insensitivity / Increased responsivness to growth hormone #604271 AD
 IGF1 deficiency IGF1 deficiency IGF1 #608747 single gene sequencing yes     see text AR
 IGF1RES IGF1 resistancy IGF1R #270450 single gene sequencing yes     see text AD, AR
Sex Development and Maturation
 DSD Disorders of sex development SRY, AR,> 30 others   1. Cytogenetics
(2. single gene sequencing)
3. multigene panel
yes yes yes   broad clinical spectrum and overlap. AD, AR, X-linked
 TS / UTS Turner syndrome 45,X   cytogenetics    100%   see text de-novo
 KS Klinefelter syndrome 47,XXY   cytogenetics    100%   see text de-novo