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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)

AcronymDisorderGene / Chromosomal RegionOMIMGenetic testing strategy*Detection on different molecular levels (rates if available)**Differential diagnosisMode of inheritance***
SNVsgene/exon targeted CNV analysisCNVsEpimut UPDs
Genetic adrenal disorders*
 ACCAdrenocortical carcinomaTP53#202300(1. sequencing of specific exons)
2. multigene panel
yesyes  ADCC can be observed in Beckwith-Wiedemann syndrome (see below) and is a component tumor in Li-Fraumeni syndrome.AD
 APS1autoimmune polyendocrine syndrome type 1AIRE#2403001. single gene testing
2. multigene panel
yesyes  Overlap with several disorders.AR, AD
 CNCCarney complexPRKAR1A#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
 PPNADPrimary pigmented nodular adrenocortical disease type 1PRKAR1A#610489AD
Primary pigmented nodular adrenocortical disease type 2PDE11A#610475yes AD
Primary pigmented nodular adrenocortical disease type 3PDE8B#614190yes AD
 21-OHD-CAH21-Hydroxylase-Deficient Congenital Adrenal HyperplasiaCYP21A2#2019101. single gene testing. CNV analysis70–80%20–30%  Major type of CAH. 
Calcium and Phosphate Homeostasis*
 HRPTHyperparathyroidismCDC73#145000Multigene panelyesyes   AD
Neonatal HyperparathyroidismCASR#239200yes  AD, AR
Familial Isolated HypoparathyroidismGCM2#146200yes  AD, AR
hypocalciuric hypercalcaemiaCASR
GNA11
AP2S21
#601198
#145981
#600740
yes  AD
 PHP / iPPSDPseudohypoparathyroidism / Inactivated PTH/PTHrP Signalling DisorderGNAS#166350 #103580 #603233 #612462 #612463Methylation-specific test single gene testing CNV analysesyesyes yesHeterogeneous group of disorders caused by molecular changes of the imprinted GNAS locus.AD
 ADHRAutosomal dominant hypophosphatemic ricketsFGF23#193100single gene testingyesyes   AD
 XLHRX-linked dominant hypophosaphatemic ricketsPHEX#307800single gene testingyesyes   X-linked
Genetic Pituitary Hormone Disorders*
 CPHDCombined Pituitary Hormone DeficiencyPROP1#262600(1. single gene testing)
2. multigene panel
yesyes  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 
 FIPAFamilial Isolated Pituitary AdenomaAIP#102200single gene testingyes   Overlap with MEN1AD,
somatic mosaicism
Genetic Thyroid Disorders* 
 HCNGCongenital non-goitrous hypothyroidismTSHR#275200multigene panelyesyes  Molecularly heterogenous group of disorders.AD, AR
SLC5A5#274400
PAX8#218700
others 
Glucose and Insulin Homeostasis*
 MODYMaturity-Onset Diabetes of the Young type 1HNF1A#600496(1. single gene testing)
2. multigene panel
3. CNV analyses
yesyes  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 2GCK#125851
Maturity-Onset Diabetes of the Young type 1HNF4A#125850
 TNDMTransient neonatal diabetes mellitus6q24 (PLAG1)#6014101. Methylation-specific test
2. single gene testing or multigene panel
noyesyesyesTNDM accounts for ~ 50% neonatal diabetes. Other genetic causes include pathogenic variants in KCNJ11 and ABCC8 (see PNDM).sporadic, AD, paternal inheritance; somatic mosaicism
KCNJ11#610582yes   AD
ABCC8#610374   ;
 PNDMPermanent neonatal diabetes mellitusKCNJ11#606176multigene panelyes   KCNJ11 mutations account for 30% of patients, INS 20% and ABCC8 19%.J55AD, AR
ABCC8
GCK
INS
PDX1
 HHF / CHIFamilial hyperinsulinemic hypoglycemia / congenital hyperinsulinismABCC8#256450(1. single gene testing)
2. multigene panel
yesyes UPD as somatic event in focal typeABCC8 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*
 MEN1Multiple endocrine neoplasia type 1MEN1#1311001. 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
 MEN2Multiple endocrine neoplasia type 2RET#1714001. testing for specific variants (C634R)
2. sequencing of whole gene
98 > 98%    AD
 MEN3Multiple endocrine neoplasia type 3#1623001. testing for specific variants (M918T)
2. sequencing of whole gene
98 > 98%AD
 MEN4Multiple endocrine neoplasia type 4CDKN1B#620755see MEN1yes   see MEN1AD
 VHLvon Hippel-Lindau syndromeVHL#1933001. single gene sequencing
2. CNV analyses
3. multigene panel
VHL: 89%VHL: 11%  broad clinical spectrum and overlap with several disorders.AD
 PPGL/PCCHereditary Paranglioma- PheochromocytomasMAX#171300multigene panel; for specific phenotypes: sequencing of SDHB, SDHDdependent on the gene: up to 100%up to 15%  Broad clinical spectrum and overlap with several disorders. It includes Cushing syndrome.AD
SDHA#614165AD
SDHAF2#601650AD
SDHB#115310AD
SDHC#605373AD
SDHD#168000AD, paternal inheritance
TMEM127#171300AD
others    
Growth, Obesity and Metabolism*
 NSNoonan syndromePTPN11#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 
 BWSBeckwith-Wiedemann syndrome11p15.5#1306501. methylation-specific test < 1% 50%Broad clinical spectrum and overlap with several disorders.sporadic, rare cases: AD; somatic mosaicism
2. CDKN1C testingsporadic: 5% familial: 50%   AD, maternal inheritance
3. multigene panelsingle cases   AD, AR, X-linked
 SRSSilver-Russell syndrome11p15.5#1808601. methylation-specific test   40%Broad clinical spectrum and overlap with several disorderssporadic, rare cases: AD; somatic mosaicism
2. Microarray  10% AD
3. WESup to 10%   AD, AR, X-linked
7methylation-specific test   10%som. Mosaic
14q32methylation-specific test   10%som. Mosaic
 PWSPrader-Willi syncdrome15q11.2#176270CNV analyses 75%  Clinical overlap with several disorderssporadic; rare cases: AD
methylation-specific test (also detects 15q11.2 CNVs) 75–80% 20–25%
 IGHDIsolated growth hormone deficiency type 1AGH1#262400single gene sequencingyes   Overlap with disorders caused by mutations in other members of the GH axis.AR
Isolated growth hormone deficiency type 1BGH1#612781AR
Isolated growth hormone deficiency type 2GH1#173100AD
Isolated growth hormone deficiency type 4GHRHR#618157single gene sequencingyes   AD
 LSLaron dwarfismGHR#262500single gene sequencingyes   AR
GHIPpartial growth hormone insensitivity / Increased responsivness to growth hormone#604271AD
 IGF1 deficiencyIGF1 deficiencyIGF1#608747single gene sequencingyes   see textAR
 IGF1RESIGF1 resistancyIGF1R#270450single gene sequencingyes   see textAD, AR
Sex Development and Maturation
 DSDDisorders of sex developmentSRY, AR,> 30 others 1. Cytogenetics
(2. single gene sequencing)
3. multigene panel
yesyesyes broad clinical spectrum and overlap.AD, AR, X-linked
 TS / UTSTurner syndrome45,X cytogenetics  100% see textde-novo
 KSKlinefelter syndrome47,XXY cytogenetics  100% see textde-novo