Table 3 Secondary findings of enrolled parents segregated into “Relevant clinical diagnoses”, “Relevant family history or symptoms”, and “No relevant family history, symptoms or clinical diagnosis”
From: Genomic sequencing identifies secondary findings in a cohort of parent study participants
Age (M/F) | Gene | Variant info | Associated phenotype (MIM) | Phenotypes or family history reported by parent participantsa |
|---|---|---|---|---|
Relevant clinical diagnoses reported (0.6% total population) | ||||
35 (F) | SLC4A1 | V488M | Spherocytosis, type 4 (612653) | Clinically diagnosed with spherocytosis; two daughters and father with spherocytosis |
37 (F) | SLC22A5 | A142S; T440M, R488H | Carnitine deficiency, systemic primary (212140) | Clinically diagnosed with carnitine deficiency |
36 (F) | PKD2 | c.1319+1G>A | Polycystic kidney disease 2 (613095) | Clinically diagnosed with polycystic kidney disease; mother, brother, two nieces, maternal aunt, uncle, and grandmother with polycystic kidney disease |
30 (F) | DSG2 | V986fs | Cardiomyopathy, dilated, 1BB; arrhythmogenic right ventricular dysplasia 10 (612877; 610193) | Clinically diagnosed with postpartum cardiomyopathy; paternal family history of arrhythmia; paternal uncle with two “heart attacks” prior to age 40 |
52 (M) | ANK2 | E1458G | Cardiac arrhythmia, ankyrin-B-related, long QT syndrome 4 (600919) | Clinically diagnosed with hypertrophic cardiomyopathy and arrhythmia; father died with ischemic heart disease |
Relevant family history or symptoms reported (1.6% of total population) | ||||
29 (F) | CLCN1 | F413C | Myotonia congenita, dominant (160800) | Leg cramps and restless legs in childhood, still occasionally has cramps; Mother diagnosed with myotonia congenita, 10 years; Maternal grandfather with a muscle biopsy performed in 30s and “stiffness” especially in cold |
35 (F) | MFN2 | W740S | Charcot–Marie–Tooth disease, axonal, type 2A2A (609260) | History of muscle wasting in back, lower extremities; brother clinically diagnosed with Charcot–Marie–Tooth, 30s; multiple family members affected with “unspecified muscle disorder” |
40 (M) | BRCA1 | G1756fs | Breast/ovarian cancer, familial 1 (604370) | Mother with breast cancer, 30s |
38 (F) | BRCA2 | c.8488-1G>A | Breast/ovarian cancer, familial 2 (612555) | Maternal grandfather with bilateral breast cancer, 60s; paternal grandmother with breast cancer, age unknown |
33 (F) | BARD1 | E652fs | Breast cancer susceptibility (114480) | Maternal great-grandmother with breast cancer, 50s; Maternal grandmother had bladder, lung, and peritoneal cancer, age unknown |
43 (M) | PMS2 | P246fs | Hereditary nonpolyposis colorectal cancer, type 4 (614337) | Father (60s) and paternal aunt (40s) had colon cancer; paternal aunt (60s) and grandmother (50s) with breast cancer |
28 (F) | SCN4A | T1313M | Paramyotonia congenita (168300) | At enrollment, no report of neuromuscular phenotypes. At return of results, indicated that she had muscle stiffness but always thought she was “easily fatigued” and had “low stamina”; mother displays similar symptoms |
41 (M) | HARS | R137Q | Charcot–Marie–Tooth, axonal, type 2W (616625) | At enrollment, no report of neuromuscular phenotypes. At return of results, indicated that he had Charcot–Marie–Tooth associated phenotypes. Always thought he was “just clumsy” |
32 (F) | KCNQ1 | R366W | Long QT syndrome 1 (192500) | Father with coronary artery disease with triple bypass, early 50s, paternal aunt with early-onset stroke, late 30s |
47 (M) | KCNQ1 | P7S | Long QT syndrome 1 (192500) | Mother “fainted” and “hit the floor”; was told this impact prevented cardiac arrest |
39 (M) | MYBPC3 | E542Q | Hypertrophic cardiomyopathy 4; dilated cardiomyopathy 1MM (115197; 615396) | “Leaky heart valve”; Dad has pacemaker and mom has “leaky heart valve,” 60s |
30 (M) | DDX41 | D140fs | Susceptibility to familial myeloproliferative/lymphoproliferative neoplasms (616871) | Paternal cousin with lymphoma “unspecified,” age unknown |
37 (F) | MC4R | C271Y | Obesity, autosomal dominant (601665) | Obese (body mass index: 41) |
No relevant family history, symptoms, or clinical diagnosis reported (0.9% of total population) | ||||
52 (F) | SCN5A | T1303M | Long QT syndrome 3 (603830) | Recommended to have cardiovascular evaluation |
50 (M) | DSG2 | E1020fs | Cardiomyopathy, dilated, 1BB; arrhythmogenic right ventricular dysplasia 10 (612877; 610193) | Recommended to have cardiovascular evaluation |
31 (M) | ACTN1 | V105I | Bleeding disorder, platelet type, 15 (615193) | Recommended to have a complete blood count and functional platelet study |
33 (M) | MSH2 | Y570fs | Hereditary nonpolyposis colorectal cancer, type 1 (120435) | Recommended to follow up and have colonoscopy |
36 (F) | BARD1 | Y404* | Breast cancer susceptibility (114480) | Recommended to discuss with physician and cancer genetic counselor |
47 (M) | BRCA2 | V220fs | Breast/ovarian cancer, familial 2 (612555) | Recommended to have self- and clinical breast exams; discuss with cancer genetic counselor |
52 (M) | RET | C609Y | Medullary thyroid carcinoma (155240); susceptibility to Hirschsprung disease 1 (142623) | Recommended to follow up and test daughter with Hirschsprung disease |
