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Biallelic variants in BRCA1 gene cause a recognisable phenotype within chromosomal instability syndromes reframed as BRCA1 deficiency.

ABSTRACT: Pathogenic variants in BRCA1 gene in heterozygous state are known to be associated with breast-ovarian cancer susceptibility; however, biallelic variants cause a phenotype recognised as Fanconi anaemia complementation group S. Due to its rarity, medical management and preventive screening measures are insufficiently understood. Here, we present nine individuals (one new and eight previously presented) with biallelic variants in BRCA1 gene, to delineate clinical features in comparison with other chromosome instability syndromes and understand the patients' health risk. Features seen in these 9 individuals (7 females/2 males) include prenatal and postnatal growth failure (9/9), microcephaly (9/9), hypo/hyperpigmented lesions (9/9), facial dysmorphism (9/9), mild developmental delay (8/9) and early-onset solid tumours (5/9). None presented bone marrow failure or immunodeficiency. Individuals with biallelic variants in BRCA1 also showed chromosomal instability by mitomycin and diepoxybutane test. The phenotype caused by biallelic BRCA1 variants is best framed between Fanconi anaemia and Nijmegen syndrome, yet distinct due to lack of bone marrow failure and immunodeficiency. We hypothesise that disease class should be reframed and medical management in people with biallelic variants in BRCA1 should emphasise on detection of solid tumour development and avoiding exposure to ionising radiation.

SUBMITTER: Chirita-Emandi A

PROVIDER: S-EPMC8394758 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes.

Project description:TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell- specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n=39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n=41; 82%) of the pa-tients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P< .001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P< .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD(-)CD27(+) B cells (P= .019), benign lymphoproliferation (P< .001), and autoimmune complications (P= .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation.

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