Identification and characterization of cryptic SHOX intragenic deletions in three Japanese patients with Léri–Weill dyschondrosteosis

Abstract

Although short-stature homeobox-containing gene (SHOX ) haploinsufficiency is responsible for Léri-Weill dyschondrosteosis (LWD), the molecular defect has not been identified in *20% of Japanese LWD patients. Furthermore, although high prevalence of microdeletions affecting SHOX is primarily ascribed to the presence of repeat sequences such as Alu elements around SHOX, it remains to be determined whether microdeletions are actually mediated by repeat sequences. We performed multiple ligation probe amplification (MLPA) assay in six Japanese LWD patients with apparently normal SHOX, followed by fluorescent in situ hybridization (FISH) analysis and sequencing for polymerase chain reaction (PCR) products encompassing the deletion junctions in patients with abnormal MLPA patterns. Consequently, heterozygous intragenic deletions were identified in three cases, i.e., a 5,906-bp deletion involving exons 4-5 in case 1, a 5,594-bp deletion involving exons 4-6a in case 2, and a 50,199-bp deletion involving exons 4-6b in case 3. The deletion breakpoints of cases 1 and 2 were present in nonrepeat sequences, whereas those of case 3 resided within Alu elements. The results suggest that cryptic SHOX intragenic deletions account for a small fraction of LWD and that microdeletions affecting SHOX can be generated by repeat-sequence-mediated aberrant recombinations and by nonhomologous end joining.

Microduplications at the pseudoautosomalSHOXlocus in autism spectrum disorders and related neurodevelopmental conditions

“…The scattered distribution of CNV breakpoints around SHOX was also already observed for SHOX deletions 59. This is thought to reflect genomic rearrangements caused by a combination of repeat-sequence-mediated aberrant recombinations and non-homologous end-joining, that is, an aberrant breakage and reunion between non-homologous sequences, that may be facilitated by the high recombination frequency in the PAR1 and by the abundant presence of repeat sequences (eg, Alu elements) 59. Consistent with the scattered breakpoint distribution, some of the microduplications identified in both cases and controls also affected other pseudoautosomal genes located upstream or downstream of SHOX .…”

“…Likewise, the SHOX microduplications identified in the present study consisted of overlapping events with variable size and non-recurrent breakpoints, distributed throughout the SHOX locus. The scattered distribution of CNV breakpoints around SHOX was also already observed for SHOX deletions 59. This is thought to reflect genomic rearrangements caused by a combination of repeat-sequence-mediated aberrant recombinations and non-homologous end-joining, that is, an aberrant breakage and reunion between non-homologous sequences, that may be facilitated by the high recombination frequency in the PAR1 and by the abundant presence of repeat sequences (eg, Alu elements) 59.…”

SHOX Haploinsufficiency as a Cause of Syndromic and Nonsyndromic Short Stature

“…SHOX haploinsufficiency is more frequently caused by CNVs than point mutations [Benito-Sanz et al, 2005, 2011, 2012aFukami et al, 2008;Chen et al, 2009;Rosilio et al, 2012]. Various submicroscopic microdeletions in PAR1 involving SHOX exons and/or its flanking regions have been identified in ISS and LWD patients.…”

Cryptic intragenic deletion of the SHOX gene in a family with Léri-Weill dyschondrosteosis detected by Multiplex Ligation-Dependent Probe Amplification (MLPA)

“…reported three patients with LWD with apparently normal SHOX according to conventional screening techniques. MLPA also detected an heterozygous deletion involving exons IV and V in one case, exons IV-VIa in the second case and exons IVVIb in the third case (8).…”

“…About two thirds of SHOX gene defects are caused by deletions (8). Fluorescence in situ hybridization (FISH) technique, microsatellite analysis and Southern blotting are the most common techniques used to identify these deletions.…”