UNEXPECTED PHENOTYPIC CHARACTERISTICS ASSOCIATED WITH SEVERE HAEMOPHILIA B IN TWO PAEDIATRIC PATIENTS WITH DELETIONS INVOLVING THE WHOLE F9 AND CONTIGUOUS GENES.

ZIEGLER B; ROSSETTI LC; HEPNER M; BONDUEL M; RADIC CP; MARCHIONE VD; NEVADO, J; SCIUCCATI G; ABELLEYRO MM; WAISMAN K; LAPUNZINA, P; DE BRASI CD

Milan

Congreso; Virtual Meeting of the International Society on Thrombosis and Haemostasis ISTH; 2020

International Society on Thrombosis and Haemostasis

Background: About 4-8% of patients with severe haemophilia B (HB) show large deletions of one or moreexons of F9. Deletions of the entire F9 often involve vicinal genes and show clinical features exceedingsevere-HB, such as intellectual disability, hypopituitarism, seizures, scoliosis, short stature, hypotonia,overweight and bilateral cryptorchidism.Aims: Understand the molecular basis of complex clinical phenotypes in two paediatric patients with severe-HB and whole F9-deletions.Methods: Both entire F9-deletions were primarily detected in hemizygous probands by lack of all 12 PCR-amplication products of F9. Dense SNP-array analysis was performed to estimate the gap extents. Guidedby each involved SNP-array coordinates, case-specic STS walking strategy allowed amplication andcharacterisation of the deletion breakpoints by Sanger sequencing.Results: Two patients with severe-HB, C1 and C2, showed large deletions of 4.39 and 3.9 Mb involving the F9and 14 and 15 nearby genes, respectively on Xq26.3-Xq27.2 and Xq27.1-Xq27.2 bands. Both patients presentreduced factor IX activity, overweight, global developmental delay and generalized hypotonia. C1 and C2share a partial or total deletion of FGF13, which was associated with overweight in the literature, and theyalso share a SOX3 deletion widely related to intellectual disability and global developmental delay. Notably,C2 only differed from C1 in the deletion of MAGEC2, which may account for the anal atresia present in C2and not in C1. MAGEC2 deletion has never been associated with anal atresia, thus far.Conclusions: Deletions involving X-linked genes in hemizygous males unequivocally associate with theexpression of gene-specic phenotypes, such as F9 deletions and HB. Ourndings provide further support tothe association of FGF13 with overweight and SOX3 with global developmental delay and generalizedhypotonia. In addition, our data suggest for therst time a causative linkage between anal atresia andMAGEC2 deletion.