Clinical Utility Gene Card

Name of the Disease (Synonyms):

16p13.11 microdeletion syndrome/ Del(16)(p13.11)/ 16p13.11 monosomy syndrome.

OMIM# of the Disease:

Not applicable.

Name of the Analysed Genes or DNA/Chromosome Segments:

16p13.11-p12.3: chr16:14.66-18.70 Mb, RefSeq NC_000016.9 (hg19 human reference sequence, February 2009, build 37).

OMIM# of the Gene(s):

Putative candidate genes: NDE1, 609449; NTAN1, not applicable.

Other genes in the critical deleted region (chr16: 15.48-16.32 Mb, GRCh37/hg19): MPV17L, not applicable; C16orf45, not applicable; KIAA0430, 614593; MYH11, 160745; FOPNL, not applicable; ABCC1, 158343; ABCC6, 603234.

Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for microdeletions at the 16p13.11 locus in diagnostic and prenatal settings and for risk assessment in relatives.

Name of the Disease (Synonyms):

1. Progressive familial intrahepatic cholestasis type 2 (PFIC2)

2. Bile salt export pump (BSEP) deficiency

3. Initially reported under the name Byler syndrome.

Byler syndrome refers to normal gamma-glutamyltransferase (GGT) level chronic intrahepatic cholestasis observed in children usually during the first year of life¹. Later, PFIC1 (Byler disease)² and PFIC2³ were identified. The terms PFIC2 or BSEP deficiency should be used preferentially.

OMIM# of the Disease:

601847

Name of the Analysed Genes or DNA/Chromosome Segments:

ATP-binding cassette sub-family B or ABCB11

Chromosome 2q24.3 – 2q31.1 (g.169487695-169596079)

OMIM# of the Gene(s):

603201

Review of the analytical and clinical validity as well as of the clinical utility of DNA-basedtesting for mutations in the ABCB11 gene in diagnostic, predictive and prenatal settings andfor risk assessment in relatives.

1. Name of the Disease (Synonyms):

Choroideremia (Tapetochoroidal dystrophy)

2. OMIM# of the Disease:

303100

3. Name of the Analysed Genes or DNA/Chromosome Segments:

CHM (formerly REP1, GGTA, RAB geranylgeranyl transferase component A or RAB GG transferase)

4. OMIM# of the Gene(s):

300390

Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the CHM gene in diagnostic, predictive and prenatal settings and for risk assessment in relatives.

Name of the disease (synonyms)

Alagille syndrome (ALGS); Alagille syndrome 1 (ALGS1); Alagille syndrome 2 (ALGS2). Other synonyms include Alagille–Watson Syndrome (AWS); cholestasis with peripheral pulmonary stenosis; arteriohepatic dysplasia (AHD); hepatic ductular hypoplasia, syndrome; Miller–Watson syndrome.^{1, 2, 3, 4}

OMIM# of the disease

ALGS1: 118450; ALGS2: 610205

Analysed genes or DNA/chromosome segments

JAG1 (Jagged1 gene; locus 20p12.2; disease ALGS1); NOTCH2 (Notch2 gene; locus 1p12-p11; disease ALGS2).

OMIM# of the gene(s)

JAG1 (601920); NOTCH2 (600275).

Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the JAG1 and NOTCH2 genes in diagnostic, predictive and prenatal settings and for risk assessment in relatives.

Name of the disease (synonyms)

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inheritable disease characterized by structural and functional abnormalities of the right ventricle (RV), with or without concomitant left ventricular (LV) disease. The diagnosis ARVC is made when a patient fulfils the recently revised criteria. Criteria encompass global and/or regional dysfunction and structural changes; repolarization abnormalities; depolarization and conduction abnormalities; arrhythmias; family history/the results of genetic testing; and tissue characterization by endomyocardial biopsy. Either localized or diffuse atrophy, with subsequent replacement by fibrous and fatty tissue mainly of the RV outflow tract, RV inflow tract and RV apex (‘triangle of dysplasia’) represent the histopathological characteristics of ARVC. Synonyms: arrhythmogenic right ventricular dysplasia (ARVD); arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D); arrhythmogenic cardiomyopathy (ACM); arrhythmogenic left-dominant cardiomyopathy; and arrhythmogenic LV cardiomyopathy (ALVC).

OMIM# of the disease

107970; 600996; 602086; 602087; 604400; 604401; 607450; 609040; 610193; 610476; 611528.

Name of the analyzed genes or DNA/chromosome segments

(1) Cytoskeletal protein genes: (a) Desmin gene (DES), locus 2q35^#; (b) Titin gene (TTN), locus 2q31.2^#. (2) Nuclear envelope protein genes: (a) Lamin A/C gene (LMNA), locus 1q22^#. (3) Desmosomal protein genes: (a) Desmocollin 2 gene (DSC2), locus 18q12.1; (b) Desmoglein 2 gene (DSG2), locus 18q12.1; (c) Desmoplakin gene (DSP), locus 6p24.3; (d) Junction plakoglobin gene (JUP), locus 17q21.2; (e) Plakophilin 2 gene (PKP2), locus 12p11.21. (4) Calcium/sodium-handling genes: (a) Phospholamban gene (PLN), locus 6q22.31^#; (b) Ryanodine receptor 2 gene (RYR2), locus 1q43*. (5) Other genes: (a) Alpha-T-catenin (CTNNA3), locus 10q21.3^#; (b) Transforming growth factor-β3 (TGFβ3), locus 14q24.3*; (c) Transmembrane protein 43 (TMEM43), locus 3p25.1.

^#Indicates gene not yet annotated as ARVC related in the OMIM database; *indicates the involvement of these genes is based on single publications and therefore controversial.

OMIM# of the gene(s)

(1) Cytoskeletal protein genes: (a) 125660 and (b) 188840^#. (2) Nuclear envelope protein genes: (a) 150330^#. (3) Desmosomal protein genes: (a) 125645; (b) 125671; (c) 125647; (d) 173325; and (e) 602861. (4) Calcium/sodium-handling genes: (a) 172405^# and (b) 180902*. (5) Other genes: (a) 607667^#; (b) 190230*; and (c) 612048.

^#Indicates gene not yet annotated as ARVC related in the OMIM database; *denotes the involvement of these genes is based on single publications and therefore controversial.

Name of the disease (synonyms):

Synonyms: Familial polymorphic ventricular tachycardia (FPVT), catecholamine-induced polymorphic ventricular tachycardia (CPVT). Includes: RYR2-related catecholaminergic ventricular tachycardia, CASQ2-related catecholaminergic ventricular tachycardia

OMIM# of the disease:

604772, 611938

Name of the analysed genes or DNA/chromosome segments:

RyR2, cardiac ryanodine receptor

OMIM# of the gene(s):

180902, 114251

Two genes are clearly associated with CPVT (RyR2 autosomal dominant, and CASQ2 autosomal recessive). Triadin mutations have been also shown in two CPVT families but data need confirmation. Therefore, clinical testing is not indicated.

Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the RyR2 gene in diagnostic, predictive and prenatal settings and for risk assessment in relatives.