Table 3.
List of the twenty-eight variants affecting or probably affecting protein function identified in 55/700 index cases
| Groups of genes | Mode of inheritance | Genes | Genomic position (hg19) | rs number | mRNA level | Protein level | Clinvar status | LOVD status | HGMD status | ACMG algorithm | Retained pathogenic status | Hetero/homozygous | Disease | OMIM | Recommended consultations | Recommanded follow-up | Number of cases with causal variant | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 132 actionable genes leading to predisposition to a later-onset disease | 59 genes recommended for return by the ACMG guidelines Kalia et al. [15]) | Autosomal dominant | BRCA2 | chr13:g.32968863C>A | rs80359200:C>A | NM_000059.3:c.9294C>G | p.(Tyr3098*) | Pathogenic | Not found | DM | Pathogenic | Affects function | hz | Breast-ovarian cancer, familial, 2 | 612555 | Gynaecologic consultation Genetic counselling | Annual mammography and breast MRI Breast ultrasound from age 30 years | 1 |
| chr13:g.32914103_32914107delAGTAA | – | NM_000059.3:c.5616_5620delAGTAA | p.(Lys1872Asnfs*2) | – | Not found | DM | Pathogenic | Affects function | hz | 1 | ||||||||
| chr13:g.32910667insA | rs276174819 | NM_000059.3:c.2175dupA | p.(Val726Serfs*25) | Pathogenic | Not found | DM | Pathogenic | Affects function | hz | 1 | ||||||||
| chr13:g.32937557_32937561delTTAAA | – | NM_000059.3:c.8218_8222delTTAAA | p.(Leu2740Glufs*22) | - | Not found | Not found | Pathogenic | Affects function | hz | 1 | ||||||||
| DSC2 | chr18:g.28662344G>A | − | NM_004949.3:c.1123C>T | p.(Arg375*) | – | Not found | DM | Pathogenic | Probably affects function | hz | Arrhythmogenic right ventricular dysplasia 11 | 610475 | Cardiologic consultation Genetic counselling | Annual ECG and cardiac ultrasound, occasional cardiac MRI Indication of medication and ICD in some patients | 1 | |||
| KCNQ1 | chr11:g.2608860C>T | – | NM_000218.2:c.1189C>T | p.(Arg397Trp) | Discordant | Effect unknown | DM | Pathogenic | Affects function | hz | Long QT syndrome 1 | 192500 | Cardiologic consultation Genetic counselling | Annual ECG Indication of medication and ICD in some patients | 1 | |||
| chr11:g.2869033G>A | rs147445322:G>A | NM_000218.2:c.1831G>A | p.(Asp611Asn) | Discordant | Not found | DM | Likely pathogenic | Probably affects function | hz | 1 | ||||||||
| chr11:g.2869078G>A | rs199472821:G>A | NM_000218.2:c.1876G>A | p.(Gly626Ser) | Pathogenic | Not found | DM | Likely Pathogenic | Probably affects function | hz | 1 | ||||||||
| MYH7 | chr14:g.23884341C>T | rs369940645:C>T | NM_000257.3:c.5422G>A | p.(Gly1808Ser) | Likely pathogenic | Not found | DM | VUS | Probably affects function | hz | Cardiomyopathy, hypertrophic, 1 | 192600 | Cardiologic consultation Genetic counselling | Annual ECG and cardiac ultrasound, Occasional cardiac MRI Indication of medication and ICD in some patients | 1 | |||
| MYL2 | chr12:g.111350901T>G | rs143139258:T>G | NM_000432.3:c.401A>C | p.(Glu134Ala) | Discordant | Effect unknown | DM | Likely pathogenic | Probably affects function | hz | Cardiomyopathy, hypertrophic, 10 | 608758 | Cardiologic consultation Genetic counselling | Annual ECG and cardiac ultrasound, occasional cardiac MRI Indication of medication and ICD in some patients | 1 | |||
| SCN5A | chr3:g.38622493C>T | rs137854617:C>T | NM_000335.4:c.3157G>A | p.(Glu1053Lys) | Discordant | Not found | DM | Likely pathogenic | Probably affects function | hz |
Long QT syndrome-3 Atrial fibrillation, familial, 10 Brugada syndrome 1 Cardiomyopathy, dilated, 1E Heart block, progressive, type IA |
603830 614022 601144 601154 113900 |
Cardiologic consultation Genetic counselling | Annual ECG and cardiac ultrasound, occasional cardiac MRI Indication of medication and ICD in some patients | 1 | |||
| chr3:g.38603958G>A | rs199473603:G>A | NM_000335.4:c.3908C>T | p.(Thr1303Met) | Pathogenic/Likely pathogenic | Not classified | DM | Likely pathogenic | Probably affects function | hz | 1 | ||||||||
| TP53 | chr17:g.7578475G>A | rs587782705:G>A | NM_000546.5:c.455C>T | p.(Pro152Leu) | Pathogenic | Not found | DM | Pathogenic | Affects function | hz |
Breast cancer Choroid plexus papilloma Colorectal cancer Li-Fraumeni syndrome |
114480 260500 114500 151623 |
Oncologic consultation Genetic counselling | Annual abdominal and breast ultrasound Annual brain and breast MRI Annual hemogram | 1 | |||
| 69 additional genes associated with medically actionable genetic conditions that might remain undiagnosed in adults (Green et al. [12]; Dorschner et al. [17]; Amendola et al. [18]; Dewey et al. [19]; the 100.000 Genomes Project Protocol v3 [20]) | Autosomal dominant | FLCN | chr17:g.17119709dupG | rs80338682 | NM_144997.5:c.1285dupC | p.(His429Profs*27) | Pathogenic | Not found | DM | Pathogenic | Affects function | hz | Birt–Hogg–Dube syndrome | 135150 | Annual dermatological consultation Genetic counselling | Annual kidney ultrasound, alterning with MRI | 1 | |
| GCH1 | chr14:g.55310817T>C | rs41298442:T>C | NM_000161.2:c.671A>G | p.(Lys224Arg) | Pathogenic | Not found | DM | VUS | Probably affects function | hz | Dystonia, DOPA-responsive, with or without hyperphenylalaninemia | 128230 | Neurological consultation Genetic counselling | Specific medication | 1 | |||
| HMBS | chr11:g.118963710dupT | – | NM_000190.3:c.891dupT | p.(Thr298Tyrfs*9) | – | Not found | DM | Pathogenic | Probably affects function | hz | Porphyria, acute intermittent | 176000 | Metabolic consultation Genetic counselling | Active prevention and treatment of crisis | 1 | |||
| MYLK | chr3:g.123457827G>A | rs778050996:G>A | NM_053025.3:c.505C>T | p.(Arg169*) | – | Not found | Not found | Pathogenic | Probably affects function | hz | Aortic aneurysm, familial thoracic 7 | 613780 | Cardiologic consultation Genetic counselling | Annual ECG and cardiac ultrasound, Occasional cardiac MRI Indication of medication and ICD in some patients | 1 | |||
| SCN3B | chr11:g.123524481A>G | rs121918282:A>G | NM_001040151.1:c.29T>C | p.(Leu10Pro) | Discordant | Not found | DM? | Pathogenic | Probably affects function | hz | Brugada syndrome 7 | 613120 | Cardiologic consultation Genetic counselling | Annual ECG Indication of medication and ICD in some patients | 2 | |||
| Ausomal recessive | HFE | chr6:g.26093141G>A | rs1800562:G>A | NM_000410.3:c.845G>A | p.(Cys282Tyr) | Discordant | Affects function | DFP | Pathogenic | Affects function | hmz | Hemochromatosis | 235200 | Gastroenterological consultation Genetic counselling | Annual blood test (ferritin, transferrin saturation coefficient) | 1 | ||
| 4 additional genes predisposing to thrombosis or haematological pathologies | Autosomal dominant | VWF | chr12:g.6143978C>T | rs41276738:C>T | NM_000552.3:c.2561G>A | p.(Arg854Gln) | Pathogenic | Affects function/probably affects function | DM | Pathogenic | Affects function | hz | Von Willebrand disease type 2 | 613554 | Haematological consultation Genetic counselling | Blood coagulation tests | 6 | |
| 113 genes for genetic counselling | 3 genes with frequent hetezozygous status in France | Autosomal recessive | CFTR | chr7:g.117199646_117199648delCTT | rs113993960 | NM_000492.3:c.1521_1523delCTT | p.(Phe508del) | Pathogenic | Not found | Not found | Pathogenic | Affects function | hz | Cystic fibrosis | 219700 | Family genetic counselling | – | 22 |
| chr7:g.117251609A>G | rs76151804:A>G | NC_000007.13(NM_000492.3):c.3140-26A>G | – | Pathogenic | Effect unknown | DM | Pathogenic | Affects function | hz | – | 1 | |||||||
| chr7:g.117227832G>T | rs113993959:G>T | NM_000492.3:c.1624G>T | p.(Gly542*) | Pathogenic | Affects function | DM | Pathogenic | Affects function | hz | – | 1 | |||||||
| chr7:g.117242922G>A | rs80224560:G>A | NC_000007.13(NM_000492.3):c.2657 + 5G>A | – | Pathogenic | Effect unknown | DM | Pathogenic | Affects function | hz | – | 1 | |||||||
| chr7:g.117292931C>G | rs80034486:C>G | NM_000492.3:c.3909C>G | p.(Asn1303Lys) | Pathogenic | Effect unknown | DM | Pathogenic | Affects function | hz | – | 1 | |||||||
| CYP21A2 | chr6:g.32007203T>A | rs6475:T>A | NM_000500.7:c.518T>A | p.(Ile173Asn) | Pathogenic | Not found | DM | Pathogenic | Affects function | hz | Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency, classic type | 201910 | Family genetic counselling | – | 1 | |||
| 110 implicated in X-linked intellectual deficiency | X-linked recessive | ARX | chrX:g.25025293_25025302delGCCCAGCGGC | – | NM_139058.2:c.1374_1383delGCCGCTGGGC | p.(Pro459*) | – | Not found | Not found | Likely pathogenic | Probably affects function | hz |
Epileptic encephalopathy, early infantile, 1 Hydranencephaly with abnormal genitalia Lissencephaly, X-linked 2 |
308350 300215 300215 |
Family genetic counselling | – | 1 | |
| GPC3 | chrX:g.132730547G>T | – | NM_001164617.1:c.1563C>A | p.(Cys521*) | – | Not found | Not found | Pathogenic | Probably affects function | hz | Simpson–Golabi-Behmel syndrome, type 1 | 312870 | family genetic counselling | – | 1 | |||
DFP disease-associated polymorphisms with supporting functional evidence, DM disease-causing mutations, DM? probable/possible pathological mutation, ECG electrocardiogram, ICD implantable cardioverter defibrillator, hz heterozygous, hmz homozygous, MRI magnetic resonance imaging, VUS variant of unknown significance