Haemophilia B, severe childhood obesity and other extra‐haematological features associated with similar 4Mb‐deletions on Xq27: Clinical findings, molecular insights and literature update

RADIC, CLAUDIA P.; ABELLEYRO, MIGUEL M.; ZIEGLER, BETIANA; MARCHIONE, VANINA D.; NEVADO, JULIÁN; LAPUNZINA, PABLO; SCIUCCATI, GABRIELA; NEME, DANIELA; ROSSETTI, LILIANA C.; BONDUEL, MARIANA; DE BRASI, CARLOS D.

HAEMOPHILIA THE OFFICIAL JOURNAL OF THE WORLD FEDERATION OF HEMOPHILIA

Blackwell Science

Año: 2023

1351-8216

Introduction: Haemophilia B (HB) is associated with pathogenic variants in F9. Hemizygousdeletions encompassing the entire F9 and proximate genes may express extra-haematological clinical phenotypes.Aim: To analyse the genotype/phenotype correlations in two unrelated boys withsevere early childhood obesity (SCO), global developmental delay (GDD) and similarbleeding phenotype associated with comparable Xq27 deletions spanning the entireF9 and proximate genes, and characterise the pathogenic events estimating the mostlikely mutationalmechanism involved.Methods: Entire F9-deletions were detected in three hemizygous unrelated probandswith 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-specificSTS walking scan allowed characterisation of the deletion breakpoints. Extensiveuse of bioinformatics, statistics and clinical databases allowed the investigation ofgenotype-phenotype associations.Results: Patients C#1/C#2 and Co resulted in a complete F9 and additional gene deletionsof 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 pituitaryhypothyroidism (PH) whilst C#2 extra-deleted gene MAGEC2 indirectly relatesto anal atresia (AA). Breakpoint analysis revealed the involvement of the mechanismsof Alu/Alu recombination for the first time in HB and non-homologous or alternativeend-joining.Conclusion: Our results represent the first report of unrelated patients with HB, SCOand GDD. This study and the literature update expand the spectrum of clinical findingsand molecular insights observed in patients withHBcaused by complete F9 and nearbySOX3 and MAGEC2 gene deletions, which may configure a contiguous gene syndrome.