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
| 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 | ||||