Unexpected phenotypic characteristics associated with severe haemophilia B in two paediatric patients with deletions involving the whole F9 and contiguous genes

RADIC CP; ABELLEYRO, M.M.; ZIEGLER, BM; MARCHIONE VD; WAISMAN K; ROSSETTI CL; NEVADO J; LAPUNZINA ; HEPNER M; SCIUCCATI G; DE BRASI C; BONDUEL M

Milan

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

International Society on Thrombosis and Haemostasis, ISTH

Background About 4-8% of patients with severe haemophilia B (HB) show large deletions of one or more exons of F9. Deletions of the entire F9 often involve vicinal genes and show clinical features exceeding severe-HB, such as intellectual disability, hypopituitarism, seizures, scoliosis, short stature, hypotonia, overweight and bilateral cryptorchidism. Aim: Understand the molecular basis of complex clinical phenotypes in two paediatric patients with severe-HB and whole F9-deletions.MethodsBoth entire F9-deletions were primarily detected in hemizygous probands by lack of all 12 PCR-amplification products of F9. Dense SNP-array analysis was performed to estimate the gap extents. Guided by each involved SNP-array coordinates, case-specific STS walking strategy allowed amplification and characterisation 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 F9 and 14 and 15 nearby genes, respectively on Xq26.3-Xq27.2 and Xq27.1-Xq27.2 bands. Both patients present reduced factor IX activity, overweight, global developmental delay and generalized hypotonia. C1 and C2 share a partial or total deletion of FGF13, which was associated with overweight in the literature, and they also 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 C2 and not in C1. MAGEC2 deletion has never been associated with anal atresia, thus far.Conclusion Deletions involving X-linked genes in hemizygous males unequivocally associate with the expression of gene-specific phenotypes, such as F9 deletions and HB. Our findings provide further support to the association of FGF13 with overweight and SOX3 with global developmental delay and generalized hypotonia. In addition, our data suggest for the first time a causative linkage between anal atresia and MAGEC2 deletion.