Molecular characterization of a 4 409 480 bp deletion of the human X chromosome in a patient with haemophilia B

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

“…Notably, a comprehensive and detailed analysis of the literature evidence compiling all entire F9 deletions expanding from Xq26.3 to Xq27.2 reaches similar conclusions about highlighting FGF13 and SOX3 as playing key roles impacting the observed phenotypes (Supplementary Figure SF3) (Nakamura et al 2016;Hewitt et al 2014;Jourdy et al 2016;Wu et al 2014).…”

“…According to the logical association, smaller deletions involving theF9 and minor extensions nearby are only associated with HB, our case#3, with full F9 and partial MCF2 deletion expressed only HB related clinical features and no additional phenotype in concordance with the literature (e.g.,Wu and Nakamura reported cases, Supplementary Figure SF3) (Nakamura et al 2016;Jourdy et al 2016;Wu et al 2014;Anson et al 1988).…”

“…For example, Jourdy et al (Jourdy et al 2016) reported five deletions including the entire F9 one of them involving from FGF13 to SPANXN4 including SOX3 and MAGEC2 among other genes and expressed overweight, hypotonia, bilateral cryptorchidism, scoliosis, mild intellectual disability (ID), special school needs and developmental delay (DD) (late walking); and three cases encompassing several genes on F9 downstream region reaching at least up toSPANXC expressing mostly severe to mild ID, special school needs, short stature, hypotonia, DD (late walking) and delayed speech acquisition, but none of them obesity (Supplementary Figure SF3). Nakamura et al (Nakamura et al 2016) and Hewitt et al (Hewitt et al 2014) reported four and one large deletions targeting the entireF9 , respectively; two of them, who showed deletions spanning all genes in the studied region, expressed seizures and ID adding scoliosis and partial hypopituitarism but there was not evidence of suffering obesity or overweight (Supplementary Figure SF3).…”

“…Due to technical reasons most large deletions are only detected in hemizygous patients but they are rarely characterized at the sequence level. However, some reported patients with deletions of the entireF9 and vicinal genes on Xq26-q27 presented additional phenotypic abnormalities different from those associated with HB, such as intellectual disability (ID), hypopituitarism, seizures, scoliosis, short stature, hypotonia, overweight, bilateral cryptorchidism (Nakamura et al 2016;Hewitt et al 2014;Jourdy et al 2016;Stoof et al 2018;Vencesla et al 2007;Alatzoglou et al 2014) while others patients only showed bleeding symptoms associated with HB (Nakamura et al 2016;Koeberl et al 1990).…”

A genetic analysis of 23 Chinese patients with hemophilia B

“…Large deletions (>50 bp) in the F9 gene, 90% of which are associated with the severe phenotype, occur in approximately 5% of patients with severe HB and significantly increased risks for developing inhibitors 5 7 8 . Although approximately 100 types of large deletions of the F9 gene have been reported, only 19 have defined breakpoints 9 10 11 . It has been proposed that the underlying mechanisms may be non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ) or microhomology-mediated break-induced recombination (MMBIR) events 10 .…”