Introduction: Haemophilia B (HB) is associated with pathogenic variants in F9. Hemizygous deletions encompassing the entire F9 and proximate genes may express extra-haematological clinical phenotypes. Aim: To analyse the genotype/phenotype correlations in two unrelated boys with severe early childhood obesity (SCO), global developmental delay (GDD) and similar bleeding phenotype associated with comparable Xq27 deletions spanning the entire F9 and proximate genes, and characterise the pathogenic events estimating the most likely mutational mechanism involved. Methods: Entire F9-deletions were detected in three hemizygous unrelated probands with HB: two cases, C#1/C#2, presented SCO and GDD and a control patient (Co), who only had severe bleeding symptoms. Dense SNP-array and case-specific STS walking scan allowed characterisation of the deletion breakpoints. Extensive use of bioinformatics, statistics and clinical databases allowed the investigation of genotype-phenotype associations. Results: Patients C#1/C#2 and Co resulted in a complete F9 and additional gene deletions of variable extensions on Xq26.3-Xq27.2 (C#1/C#2/Co: 4.3Mb/3.9Mb/160Kb). C#1/C#2 common deleted gene SOX3 is directly associated with SCO, GDD and pituitary hypothyroidism (PH) whilst C#2 extra-deleted gene MAGEC2 indirectly relates to anal atresia (AA). Breakpoint analysis revealed the involvement of the mechanisms of Alu/Alu recombination for the first time in HB and non-homologous or alternative end-joining. Conclusion: Our results represent the first report of unrelated patients with HB, SCO and GDD. This study and the literature update expand the spectrum of clinical findings
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. 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
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