Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions

Abstract

Background X linked intellectual disability (XLID) is common, with an estimated prevalence of 1/1000. The expanded use of array comparative genomic hybridisation (CGH) has led to the identification of several XLID-associated copy-number variants. Methods Array CGH analysis was performed using chromosomal microarray with w105 000 oligonucleotides covering the entire genome. Confirmatory fluorescence in situ hybridisation analyses were subsequently performed. Chromosome X-inactivation (XCI) was assessed using methylation-sensitive restriction enzyme digestion followed by PCR amplification. Results A novel w0.5 Mb duplication in Xq28 was identified in four cognitively impaired males who share behavioural abnormalities (hyperactivity and aggressiveness) and characteristic facial features (high forehead, upper eyelid fullness, broad nasal bridge and thick lower lip). These duplications were inherited from mothers with skewed XCI and are mediated by nonallelic homologous recombination between the low-copy repeat regions int22h-1 and int22h-2, which, in addition to int22h-3, are also responsible for inversions disrupting the factor VIII gene in haemophilia A. In addition, we have identified a reciprocal deletion in a girl and her mother, both of whom exhibit normal cognition and completely skewed XCI. The mother also had two spontaneous abortions. Conclusions The phenotypic similarities among subjects with int22h-1/int22h-2-mediated Xq28 duplications suggest that such duplications are responsible for a novel XLID syndrome. The reciprocal deletion may not be associated with a clinical phenotype in carrier females due to skewed XCI, but may be lethal for males in utero. Advancements in array CGH technology have enabled the identification of such small, clinically relevant copy-number variants.

Intron 22 homologous regions are implicated in exons 1–22 duplications of the F8 gene

“…These duplications are probably not associated with HA, as they coexisted with other molecular defects clearly responsible for HA. Contrary to a previous report and based on our study results, 21 these duplications do not appear to be associated with intellectual disability.…”

“…However, a new 0.5-Mb reciprocal deletion between int22h-1 and int22h-2 copies was reported in a normal female. As suggested by Pegoraro et al 27 and El-Hattab et al 21 , these deletions may be lethal for males in utero but have no phenotypic consequences in females, as they result in completely skewed chromosome X inactivation. As CGH is an increasingly used screening method in prenatal diagnosis and patients with cognitive and behavioral abnormalities, this 0.5 Mb deletion or the corresponding duplication is likely to be increasingly (a) Misalignment of two normal maternal X chromatids during meiosis, which may result in a NAHR mechanism in an unequal crossing over that provides copies with the duplication of 0.5 Mb between the int22h-1 and int22h-2 copies or the deletion of 0.5 Mb.…”

“…Again, after complete gene sequencing we concluded that the severe HA phenotype of case 2 was caused by classical intron 22 inversion. In the study by El-Hattab et al 21 , the index case of family 3 presented, along with his intellectual disability, a minor HA type with FVIII levels estimated at 24%. The complete sequencing of the F8 gene revealed hemizygosity for the point mutation c.6089G4A (p.Ser2030Asn), which was associated with mild HA (HADB (aka HAMSTeRS) http:// hadb.org.uk/).…”

“…publication 21 reported novel 0.5 Mb duplications between int22h-1 and int22h-2 copies in three unrelated males, presenting cognitive impairment, behavioral abnormalities, recurrent infections, and characteristic facial features. Our report describes the same rearrangement in two patients (cases 1 and 3), both presenting a large duplication of F8 gene exons 1-22 extending from int22h-1 to int22h-2 repeats.…”

NAHR-mediated copy-number variants in a clinical population: Mechanistic insights into both genomic disorders and Mendelizing traits

“…For example, the thrombocytopenia-absent radius syndrome (TAR, MIM# 274000) region on 1q21 (Klopocki et al 2007;Albers et al 2012) and the 1q21.1 deletion/duplication syndrome region (MIM# 612474, 612475) (Brunetti-Pierri et al 2008;Mefford et al 2008) found in neuropsychiatric traits such as schizophrenia and autism (The International Schizophrenia Consortium 2008; Stefansson et al 2008), in addition to three adjacent regions on chromosome 2q12.2q13 (Liu et al 2012), were collapsed in previous reports but were separated by our analyses. Moreover, using the less stringent criterion for the length of flanking DP-LCRs copies, we have identified the STS deletions and duplications on Xp22.31 (MIM# 308100) (Hernández-Martín et al 1999;Liu et al 2011) that were not included in the analysis by Cooper et al (2011) and CNVs in Xq28 (El-Hattab et al 2011) that were not detected by the approach used by Liu et al (2012).…”