Phenotype | Summary n=9 individuals | Domchek et al Dec 20122 | Sawyer et al Dec 20135 | Freire et al Nov 20173 | Seo et al
A.II.1 Apr 20186 | Seo et al
A.II.4 Apr 20186 | Seo et al
B.II.2 Apr 20186 | Seo et al
B.II.4 Apr 20186 | Keupp et al Jun 20194 | Present case 2020 |
Genotype | 5/9 homozygous | Compound heterozygous | Compound heterozygous | Homozygous | Homozygous | Homozygous | Homozygous | Homozygous | Compound heterozygous | Compound heterozygous |
BRCA1 transcript | Various | c.2457delC/ c.5207T>C in trans | c.594_597del/ c.5095C>T in trans | c.2709T>A | c.1115G>A | c.1115G>A | c.1292T>G | c.1292T>G | c.181T>G/c.5096G>A in trans | c.2933dupA/c.843_846delCTCA in trans |
BRCA1 protein product | Various | p.(Asp821Ilefs*25)/p.(Val1736Ala) | p.(Ser198Argfs*35)/p.(Arg1699Trp) | p.(Cys903*) | p.(Trp372Ter) | p.(Trp372Ter) | p.(Leu431Ter) | p.(Leu431Ter) | p.(Cys61Gly)/p.(Arg1699Gln) | p.(Tyr978Ter)/p.(Ser282TyrfsTer15) |
Genetic test for diagnosis | Panel or WES | NA | WES | WES | Panel 241 genes | Panel 241 genes | WES | WES | Panel 30 genes TruRisk | Panel 4813 genes TruSightOne |
Gender | 2/9 male | Female | Female | Female | Female | Female | Male | Female | Female | Male |
Karyotype | Normal 9/9 | 46,XX | 46,XX | 46,XX | 46,XX | 46,XX | 46,XY | 46,XX | 46,XX | 46,XY |
Age at follow-up (years) | 2–31 | 28 | 25 | 3.7 | 5 | 8 | 15.5 | 7 | 31 | 2 |
Growth failure prenatal | 8/9 yes | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | Yes |
Weight for gestational age, birth weight (g) and SD | 6/8 term | NA | SGA, term, 1990g | SGA, term, 1630 g, length 39.5 cm (−5.5 SD) | SGA, 33 weeks, 1470 g | AGA, 38 weeks, 2790 g | SGA, term, 1600 g | AGA, 2900 g | NA | SGA 37 weeks,1810 g, length 45 cm (−2 SD) |
Growth failure postnatal height SD | 9/9 yes moderate to severe | Adult height 150 cm (−2.1 SD) | Adult height 135 cm (−4.35) | At 2.5 years, height 68 cm (−6.1 SD) | At 5 years, height 92 cm (−3.6 SD) | Failure to thrive | Height <3rd percentile | Height <3rd percentile | Adult height 150 cm (−2.1 SD) | At 2 years, height 70 cm (−5.3 SD) |
Microcephaly | 9/9 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
Head circumference percentile | 8/8 Disproportional microcephaly | NA | At birth 27 cm (−5.8 SD), adult HC 48.5 cm (−4.5 SD) | At birth 25 cm (−7.7 SD) | At 5 years, HC 39 cm (−7.6 SD) | NA | NA | NA | Adult 52 cm (−2 SD) | 28 cm at birth (−5 SD) 36 cm at 2 years (−8.1 SD) |
Developmental delay IQ | 8/9 mild | Yes, delayed speech at age 4 years | Yes IQ=NA | Yes IQ=NA | Yes IQ=NA | Yes, mild IQ=NA | Yes (IQ: 50–69) | Yes (IQ: 62) | No | Yes mild |
Eye anomaly | Microphtalmia, blepharophimosis | NA | Blepharophimosis | Long eyelashes | Microphthalmia | Microphthalmia | Microphthalmia | Microphthalmia | NA | Microphthalmia |
Ear anomaly | 5/8 yes | NA | Yes | Yes | No | Cupped ears | No | No | Yes, low set | Cupped ears |
Palpebral slanting | 5/7 upslanting | NA | Upslanting | Upslanting | Upslanting | Upslanting | No | No | NA | Upslanting |
Epicanthus | 3/7 yes | NA | Yes | No | No | Yes | No | No | NA | Yes |
Strabismus | 2/9 yes | No | Yes | No | No | No | No | No | No | Yes |
Bulbous nose | 3/8 yes | Yes, small alae nasi | No | Yes | No | No | No | No | No | Yes |
Forehead | Bitemporal narrowing 3/4 | Anterior hairline low | Bitemporal narrowing | Bitemporal narrowing | NA | NA | NA | NA | NA | Bitemporal narrowing |
Coarse facial features | 2/4 yes | Yes | No | Yes (possibly due to ethnicity) | NA | NA | NA | NA | No | no |
Inferior segment face | 5/9 micrognathia | Macrognathia | Narrow palate, dental malocclusion | Micrognathia | Micrognathia | Micrognathia | NA | NA | Triangular face | Micrognathia |
Skin pigment lesions | 8/9 yes | NA | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
Hypopigmentated spots | 6/8 yes | NA | Yes | No | Yes | Yes | Yes | Yes | No | Yes |
Hyperpigmentated spots | 8/8 yes | NA | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
Limb defect | 6/8 yes | No | Camptodactyly, 2–3 toe syndactyly | Clinodactyly | Small oedematous palms, soles | Small palms | Hypoplastic thumb | No | No | Clinodactyly |
Hearing loss | 2/8 yes | NA | Yes | No | No | No | No | No | Yes (right side) | No |
Other | Undescended testes, joint laxity, heart defect, gastrointestinal and skeletal involvement | NA | Sparse hair, high-pitched voice, duodenal stenosis, joint laxity, delayed bone age | Atrial septal defect | Optic nerve hypoplasia, bilateral hip dysplasia | Right first rib hypoplasia; left 11 ribs, short neck | Right undescended testis, adrenal insufficiency | Heart defect (ASD and VSD), growth hormone deficiency | Coeliac disease and congenital hip dislocation (left side) | Wide-set nipples, micropenis, bilateral undescended testis, persistent ductus arteriosus |
Reported deceased | 2/9 deceased at the time of presentation | Yes, 6 months after diagnosis of ovarian cancer | No | No | Yes at 5 years | No | No | No | No | No |
Chromosomal breakage spontaneous | 6/6 no, various types of reporting results | NA | 0% vs 0% in control | 0.12 vs 1.0 in control | 13.3% vs 6.6% in control | NA | 6% vs 0 in control | 2% vs 0 in control | NA | No |
Chromosomal breakage Induced 0.2 µg/mL DEB | 7/8 yes, various types of reporting results | NA | 30% vs 0% in control | 1.9 vs 1.0 in control | 70% vs 7% | 32% vs 8% in control | 1.44 vs 1.0 in control | 2.14 vs 1.0 in control | 6% of cells, 0.12 breaks/cell within the normal range | 1.67 vs 1.0 in control |
Chromosomal breakage Induced MMC | 3/3 yes | NA | Increased radial chromosomes vs control | NA | NA | 92% vs 34% in control | NA | NA | NA | 80% vs 20% in control |
Malignancy yes/no | 5/9 at the time of diagnosis | Yes | Yes | No | Yes | No | No | Yes | Yes | No |
Cancer type | Breast, ovarian cancer, ALL, neuroblastoma | Ovarian cancer | Ductal breast carcinoma | – | T-cell acute lymphoblastic leukaemia | – | – | Neuroblastoma | invasive‐ductal breast carcinoma | – |
Age of cancer (years) | 2–30 | 28 | 23 | – | 5 | – | – | 2 | 30 | – |
Other | Unclear sensitivity to chemotherapy | Hypersensitivity to chemotherapy Carboplatin | No hypersensitivity to chemotherapy | Hematotoxicity due to chemotherapy | – | |||||
Bone marrow failure | 9/9 no | No | No | No | No | No | No | No | No | No |
Cancer family history | Burden of breast, ovarian, uterine, urological, lung, intestinal, prostate cancer | Breast, ovarian and peritoneal cancer in 1st and 3rd degree relatives | Ovarian in 1st and 2nd degree relatives, lung, endometrial, skin 2nd and 3rd degree relatives | Breast cancer | Intestinal and urological cancer, 2nd and 3rd degree relatives | Intestinal and urological cancer, 2nd and 3rd degree relatives | Uterine, oesophageal, and lung cancer, 2nd and 3rd degree relatives | Uterine, oesophageal and lung cancer, 2nd and 3rd degree relatives | Prostate cancer, breast cancer in 3rd degree relatives | Breast cancer in 3rd degree relatives |
SD calculated using WHO standards and reference.
.AGA, appropriate for gestational age; ALL, acute lymphoblastic leukaemia; ASD, atrial septal defect; DEB, diepoxybutane; HC, head circumference; MMC, mitomycin C; n, number; NA, not available; SGA, small for gestational age; VSD, ventricular septal defect; WES, whole exome sequencing.