Prenatal genetic testing for familial severe congenital protein C deficiency

Abstract

Severe congenital protein C (PC) deficiency is an autosomal recessive hereditary thrombophilia caused by mutations in PROC. The case manifested severe purpura fulminans, intracranial thrombosis or hemorrhage within 4 days after birth, resulting in blindness. We report the identification of inherited compound heterozygous mutations, including a novel nonsense mutation in PROC, and a prenatal genetic test for a subsequent pregnancy. Prenatal diagnosis may facilitate preemptive and radical therapy for severe PC deficiency.

The clinical presentation and genotype of protein C deficiency with double mutations of the protein C gene

“…The search terms were congenital, inherited, hereditary or heritable PC deficiency, compound heterozygous, PF, and thrombophilia. We collected 22 PC‐deficient patients for our analysis, including 12 from our cohort and 10 from the extensive review …”

Cascade health service use in family members following genetic testing in children: a scoping literature review

“… Author [ref.] Study location Disease state Focus of study Proband population Included relatives Main findings/conclusions Tairaku et al [ 29 ] Japan • Severe congenital protein C deficiency • Outcome of prenatal diagnosis in sibling of affected child • 1 child, aged 3 years 1 foetus in utero Foetus: • Heterozygous carrier; would not experience symptoms Gorakshakar and Colah [ 13 ] India • β-thalassaemia • Uptake and results of cascade screening • Paediatric, number of affected children not specified 490 children from “high risk” communities, ages not reported • 691 relatives from 44 families, including 25 siblings of index cases Children from “high risk” communities: • 96/490 (20%) heterozygotes Relatives: • Among siblings of index cases, 10/25 (40%) heterozygotes Baig et al [ 30 ] Pakistan • β-thalassaemia • Cascade genetic testing results • 1 child, age not reported • 27 relatives Relatives: • 44.4% carriers Cadet et al [ 28 ] France • HH • Yield of cascade testing and screening of at-risk adults identified through neonatal screening of infants • Neonatal (number not specified) • 11 families of C282Y a homozygous infants • 10 families of heterozygous infants • Number/type of relatives not described Families of homozygous infants: • 5 relatives from 4 families homozygous Families of heterozygous infants: • 5 relatives from 2 families homozygous • 6/10 homozygous relatives began treatment; 4/10 homozygous relatives under surveillance HH hereditary hemochromatosis. a HH-conferring variant.…”

“…Four studies addressed haematologic conditions such as hereditary hemochromatosis (HH) [ 28 ], severe congenital protein C deficiency [ 29 ], and β-thalassaemia [ 13 , 30 ] (Table 2 ). Cadet et al [ 28 ] explored the effectiveness of “reverse cascade screening” to identify adults at risk for HH.…”

Genetic and Molecular Testing in Thrombosis and Hemostasis: Informing Surveillance, Treatment, and Prognosis

“…56 The frequencies differ between racial groups, with factor V Leiden and prothrombin gene mutations found in very low frequencies in African and Asian populations. 57,58 Genetic testing for individual thrombophilias has been a standard practice, with numerous laboratories offering convenient services to clinicians who encounter VTE in their clinical practice. Early adoption of testing for factor V Leiden and prothrombin G20210A promised to identify individuals at risk of recurrence for targeted further intervention, but subsequent data have not supported such an approach.…”

“…Target sequencing of the PROC gene for any of the 200 mutations associated with protein C deficiency is confirmatory, allowing for swift initiation of treatment, but also allows testing (and treatment) of the parents and opens up the option for genetic counseling when future pregnancies are being considered. 58 There is growing appreciation that there may be more, yet to be discovered genetic mutations leading to a predisposition to VTEs. Individuals with clinical thrombophilia may have negative results when tested for the known inherited thrombophilias.…”