Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats

Abstract

We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3 to 12 Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that nonallelic homologous recombination (NAHR) caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional copy number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay (DD) and/or intellectual disability (ID) as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with deletion, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, epilepsy, ataxia, dysphagia, nystagmus, and ptosis may result from deletion of the CHAT gene, encoding choline acetyltransferase, and the SLC18A3 gene, mapping in the first intron of CHAT and encoding vesicular acetylcholine transporter. The phenotypic diversity and presence of the deletion in apparently normal carrier parents suggest that subjects carrying 10q11.21q11.23 deletions may exhibit variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and nongenetic modifiers.

Abolition of lemniscal barrellette patterning in Prrxl1 knockout mice: Effects upon ingestive behavior

“…In addition to the importance of trigeminal orosensation, in humans the location of DRGX on the chromosome, 10q11.23, is a mutation hotspot, known to be especially prone to mutations, many of which cause dysphagia (Liehr et al 2009;Ghai et al 2011;Stankiewicz et al 2012). One disorder localized to this area is Cockayne syndrome, a genetically and phenotypically heterogeneous developmental disorder characterized by poor growth, feeding disorder, progressive neurological dysfunction, and UV sensitivity (Weidenheim et al 2009).…”

Variants in SLC18A3 , vesicular acetylcholine transporter, cause congenital myasthenic syndrome

“…Recurrent deletions and reciprocal duplications involving CHAT and SLC18A3 have been previously reported and range in size from 0.12 to 12 Mb. 18,19 The clinical features associated with these changes were variable but included developmental delay and intellectual disability. However, in more than half of the patients, the deletion was present in an unaffected parent, suggesting that it either is not pathogenic when heterozygous or is associated with variable expressivity.…”

“…Two of 19 patients were reported to have ptosis, but none had other features suggestive of a congenital myasthenic syndrome, strongly suggesting that heterozygous deletion of CHAT and SLC18A3 does not cause congenital myasthenic syndrome. 19 Accordingly, heterozygous SLC18A3 mice (VAChT wt/del ) 13 and heterozygous CHAT mice (chat 1/2 ) showed reduced protein expression but did not have neuromuscular defects, and chat 1/2 mice exhibited no cognitive deficits. 20 Thus, the c.557 G.C; p.(Gly186Ala) missense variant in SLC18A3 identified in patient 1, inherited in trans to the 10q11.21-q11.23 deletion, and the homozygous c.1192G.C, p.(Asp398His) identified in patient 2 are considered the cause of congenital myasthenic syndrome in these patients, likely resulting from defective uptake of acetylcholine into presynaptic vesicles.…”

How chromosomal deletions can unmask recessive mutations? Deletions in 10q11.2 associated with CHAT or SLC18A3 mutations lead to congenital myasthenic syndrome

“…Recurrent 10q11.21‐q21.1 deletions range from 0.3 to 12 megabases (Mb) in size and are mediated by low‐copy repeats (Stankiewicz et al, ). They have been described in asymptomatic individuals as well as in patients showing intellectual disability eventually associated with a wide range of neurological features.…”