Abstract
We report a genomic and phenotypic delineation for two chromosome regions with candidate genes for syndromic intellectual disability at 12q12 and Xp22.31, segregating independently in one family with four affected members. Fine mapping of three affected members, along with six unreported small informative CNVs, narrowed down the candidate chromosomal interval to one gene LRRK2 at 12q12. Expression studies revealed high levels of LRRK2 transcripts in the whole human brain, cerebral cortex and hippocampus. RT-qPCR assays revealed that LRRK2 transcripts were dramatically reduced in our microdeletion patient DGDP289A compared to his healthy grandfather with no deletion. The decreased expression of LRRK2 may affect protein–protein interactions between LRRK2 and its binding partners, of which eight have previously been linked to intellectual disability. These findings corroborate with a role for LRRK2 in cognitive development, and, thus, we propose that intellectual disability and autism, displayed in the 12q12 microdeletions, are likely caused by LRRK2. Using another affected member, DGDP289B, with a microdeletion at Xp22.31, in this family, we performed the genomic and clinical delineation with six published and nine unreported cases. We propose HDHD1 and PNPLA4 for X-linked intellectual disability in this region, since their high transcript levels in the human brain substantiate their role in intellectual functioning.
Highlights
Comparative deletion mapping is a powerful strategy to narrow down chromosomal regions of interest to identify underlying disease-causing gene(s) [1,2,3,4,5,6,7,8]
Genomic and clinical delineation has enabled the dissection of this region, allowing for the identification of intellectual disability and craniofacial candidate genes YAF2 (MIM 607534) and PRICKLE1 (MIM 608500), while haploinsufficiency of NELL2 (MIM 602320) and DBX2 are suggested to be the cause of psychomotor delay and motor delay, respectively [13,14,15]
We provide supporting data of the pathogenicity of the 12q12 and Xp22.31 microdeletions in neurological phenotype through comparative deletion mapping and expression analysis
Summary
Comparative deletion mapping is a powerful strategy to narrow down chromosomal regions of interest to identify underlying disease-causing gene(s) [1,2,3,4,5,6,7,8]. With the availability of high-resolution microarray technology, an increasing number of pathogenic copy number variations (CNVs) responsible for recognizable syndromes are being discovered [9,10,11]. These microdeletion and microduplication syndromes are often associated with intellectual disability, autism spectrum disorders, and multiple congenital anomalies [9,11,12]. Chromosome interval 12q12 is 8.2 Mb in size, containing 28 annotated genes Interstitial deletions of this region are rare, having only been reported in six patients to our knowledge [13,14,15,16,17,18]. Genomic and clinical delineation has enabled the dissection of this region, allowing for the identification of intellectual disability and craniofacial candidate genes YAF2 (MIM 607534) and PRICKLE1 (MIM 608500), while haploinsufficiency of NELL2 (MIM 602320) and DBX2 are suggested to be the cause of psychomotor delay and motor delay, respectively [13,14,15]
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