Table 1

Characteristic features of people with biallelic BRCA1 pathogenic variants

PhenotypeSummary n=9 individualsDomchek 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
Genotype5/9 homozygousCompound heterozygousCompound heterozygousHomozygousHomozygousHomozygousHomozygousHomozygousCompound heterozygousCompound heterozygous
BRCA1 transcriptVariousc.2457delC/
c.5207T>C in trans
c.594_597del/ c.5095C>T in transc.2709T>Ac.1115G>Ac.1115G>Ac.1292T>Gc.1292T>Gc.181T>G/c.5096G>A in transc.2933dupA/c.843_846delCTCA in trans
BRCA1 protein productVariousp.(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 diagnosisPanel or WESNAWESWESPanel 241 genesPanel 241 genesWESWESPanel 30 genes TruRiskPanel 4813 genes TruSightOne
Gender2/9 maleFemaleFemaleFemaleFemaleFemaleMaleFemaleFemaleMale
KaryotypeNormal 9/946,XX46,XX46,XX46,XX46,XX46,XY46,XX46,XX46,XY
Age at follow-up (years)2–3128253.75815.57312
Growth failure prenatal8/9 yesYesYesYesYesNoYesYesYesYes
Weight for gestational age, birth weight (g) and SD6/8 termNASGA, term, 1990gSGA, term, 1630 g, length 39.5 cm (−5.5 SD)SGA, 33 weeks, 1470 gAGA, 38 weeks, 2790 gSGA, term, 1600 gAGA, 2900 gNASGA 37 weeks,1810 g, length 45 cm (−2 SD)
Growth failure postnatal height SD9/9 yes moderate to severeAdult 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 thriveHeight <3rd percentileHeight <3rd percentileAdult height 150 cm (−2.1 SD)At 2 years, height 70 cm (−5.3 SD)
Head circumference percentile8/8 Disproportional microcephalyNAAt 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)NANANAAdult 52 cm (−2 SD)28 cm at birth (−5 SD)
36 cm at 2 years (−8.1 SD)
Developmental delay
8/9 mildYes, delayed speech at age 4 yearsYes
Yes, mild
(IQ: 50–69)
(IQ: 62)
NoYes mild
Eye anomalyMicrophtalmia, blepharophimosisNABlepharophimosisLong eyelashesMicrophthalmiaMicrophthalmiaMicrophthalmiaMicrophthalmiaNAMicrophthalmia
Ear anomaly5/8 yesNAYesYesNoCupped earsNoNoYes, low setCupped ears
Palpebral slanting5/7 upslantingNAUpslantingUpslantingUpslantingUpslantingNoNoNAUpslanting
Epicanthus3/7 yesNAYesNoNoYesNoNoNAYes
Strabismus2/9 yesNoYesNoNoNoNoNoNoYes
Bulbous nose3/8 yesYes, small alae nasiNoYesNoNoNoNoNoYes
ForeheadBitemporal narrowing 3/4Anterior hairline lowBitemporal narrowingBitemporal narrowingNANANANANABitemporal narrowing
Coarse facial features2/4 yesYesNoYes (possibly due to ethnicity)NANANANANono
Inferior segment face5/9 micrognathiaMacrognathiaNarrow palate, dental malocclusionMicrognathiaMicrognathiaMicrognathiaNANATriangular faceMicrognathia
Skin pigment lesions8/9 yesNAYesYesYesYesYesYesYesYes
Hypopigmentated spots6/8 yesNAYesNoYesYesYesYesNoYes
Hyperpigmentated spots8/8 yesNAYesYesYesYesYesYesYesYes
Limb defect6/8 yesNoCamptodactyly, 2–3 toe syndactylyClinodactylySmall oedematous palms, solesSmall palmsHypoplastic thumbNoNoClinodactyly
Hearing loss2/8 yesNAYesNoNoNoNoNoYes (right side)No
OtherUndescended testes, joint laxity, heart defect, gastrointestinal and skeletal involvementNASparse hair, high-pitched voice, duodenal stenosis, joint laxity, delayed bone ageAtrial septal defectOptic nerve hypoplasia, bilateral hip dysplasiaRight first rib hypoplasia; left 11 ribs, short neckRight undescended testis, adrenal insufficiencyHeart defect (ASD and VSD), growth hormone deficiencyCoeliac disease and congenital hip dislocation (left side)Wide-set nipples, micropenis, bilateral undescended testis, persistent ductus arteriosus
Reported deceased2/9 deceased at the time of presentationYes, 6 months after diagnosis of ovarian cancerNoNoYes at 5 yearsNoNoNoNoNo
Chromosomal breakage spontaneous6/6 no, various types of reporting resultsNA0% vs 0% in control0.12 vs 1.0 in control13.3% vs 6.6% in controlNA6% vs 0 in control2% vs 0 in controlNANo
Chromosomal breakage
Induced 0.2 µg/mL DEB
7/8 yes, various types of reporting resultsNA30% vs 0% in control1.9 vs 1.0 in control70% vs 7%32% vs 8% in control1.44 vs 1.0 in control2.14 vs 1.0 in control6% of cells, 0.12 breaks/cell within the normal range1.67 vs 1.0 in control
Chromosomal breakage
Induced MMC
3/3 yesNAIncreased radial chromosomes vs controlNANA92% vs 34% in controlNANANA80% vs 20% in control
Malignancy yes/no5/9 at the time of diagnosisYesYesNoYesNoNoYesYesNo
Cancer typeBreast, ovarian cancer, ALL, neuroblastomaOvarian cancerDuctal breast carcinomaT-cell acute lymphoblastic leukaemiaNeuroblastomainvasive‐ductal breast carcinoma
Age of cancer (years)2–3028235230
OtherUnclear sensitivity to chemotherapyHypersensitivity to chemotherapy CarboplatinNo hypersensitivity to chemotherapyHematotoxicity due to chemotherapy
Bone marrow failure9/9 noNoNoNoNoNoNoNoNoNo
Cancer family historyBurden of breast, ovarian, uterine, urological, lung, intestinal, prostate cancerBreast, ovarian and peritoneal cancer in 1st and 3rd degree relativesOvarian in 1st and 2nd degree relatives, lung, endometrial, skin 2nd and 3rd degree relativesBreast cancerIntestinal and urological cancer, 2nd and 3rd degree relativesIntestinal and urological cancer, 2nd and 3rd degree relativesUterine, oesophageal, and lung cancer, 2nd and 3rd degree relativesUterine, oesophageal and lung cancer, 2nd and 3rd degree relativesProstate cancer, breast cancer in 3rd degree relativesBreast 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.