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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