Syndromic cases of hemophilia B and morbid obesity due to contiguous
gene deletions on Xq26.3-q27.2: unsuspected phenotype-genotype
associations by bioinformatics and extensive clinical data mining
Hemophilia B (HB) associates with pathogenic F9-variants. The literature
showed that hemizygous deletions encompassing F9 and vicinal genes may
express extra-phenotypes suggesting new causal relationships. Aim:
Analyze the molecular basis of syndromic cases of HB, obesity (OB),
severe global developmental delay (SGDD) and generalized hypotonia (GH).
Whole F9-deletions were detected in 3 hemizygous probands with HB. Dense
SNP-array and case-specific STS walking strategies allowed amplification
and characterization of the deletion breakpoints.
Bioinformatic/statistical analyses included data mining in HPO (Human
Phenotype Ontology), OMIM, STRING (protein-protein interaction networks)
databases and estimation of null-hypothesis-based Expected-values.
Patients (cases#3-case#1) showed complete F9 deletions involving
0.16-4.34-Mb and 1-17 additional genes on Xq26.3-q27.2.
Bioinformatic/statistical approaches revealed highly significant
STRING-associations (P≤0.00115) between case#1/#2 common deleted genes
(SOX3, FGF13, CXorf66) and those HPO associated with OB (20/343), GH
(36/923) and SGDD (10/119). Only case#2 showed two extra-phenotypic
abnormalities, anal atresia and pituitary hypothyroidism, and one
extra-deleted gene, MAGEC2. Our bioinformatic/statistical approaches
confirmed a previous involvement of SOX3 in OB suggesting additional
roles in GH and SGDD, similar to FGF13 and CXorf66 (experimentally
linked to POMGNT1, HPO-connected with all 3 phenotypes). Our findings
highlight the importance to characterize X-chromosome deletion syndromes
to unveil functional associations of the involved genomic regions.