De novo and rare inherited copy-number variations in the hemiplegic form of cerebral palsy

Abstract

PurposeHemiplegia is a subtype of cerebral palsy (CP) in which one side of the body is affected. Our earlier study of unselected children with CP demonstrated de novo and clinically relevant rare inherited genomic copy-number variations (CNVs) in 9.6% of participants. Here, we examined the prevalence and types of CNVs specifically in hemiplegic CP.MethodsWe genotyped 97 unrelated probands with hemiplegic CP and their parents. We compared their CNVs to those of 10,851 population controls, in order to identify rare CNVs (<0.1% frequency) that might be relevant to CP. We also sequenced exomes of “CNV-positive” trios.ResultsWe detected de novo CNVs and/or sex chromosome abnormalities in 7/97 (7.2%) of probands, impacting important developmental genes such as GRIK2, LAMA1, DMD, PTPRM, and DIP2C. In 18/97 individuals (18.6%), rare inherited CNVs were found, affecting loci associated with known genomic disorders (17p12, 22q11.21) or involving genes linked to neurodevelopmental disorders.ConclusionWe found an increased rate of de novo CNVs in the hemiplegic CP subtype (7.2%) compared to controls (1%). This result is similar to that for an unselected CP group. Combined with rare inherited CNVs, the genomic data impacts the understanding of the potential etiology of hemiplegic CP in 23/97 (23.7%) of participants.

Genome-wide copy number variation analysis identifies novel candidate loci associated with pediatric obesity

“…Multiple algorithms were used for CNV calling (for details regarding algorithms, see also Supplementary Table 2). We defined CNVs as high quality (predicted by at least two algorithms, spanning at least five consecutive probes, greater than 10 kb in size and overlap <75% of segmental duplication) and rare (present in <0.1% of population controls) according to previously described criteria [13][14][15][16]. To identify rare CNVs, we first compared proband CNV calls with platform-matched control data sets and then subsequently with remaining control data sets.…”

“…Our control dataset comprises of 10,851 unique subjects, majority of them with European ancestry, genotyped on multiple platforms including the Affymetrix Genome-wide Human SNP Array 6.0, Illumina HumanOmni2.5, and Affymetrix CytoScan HD. Further details regarding these samples are described elsewhere [15,16]. DNA was also extracted from the saliva of eight parents of the 52 probands (both parents were available for three cases and only the mother for five cases).…”

Genetic mimics of cerebral palsy

“…Facial dysmorphism and congenital microcephaly are additional features that should prompt CGH microarray analysis. Pathogenic de novo copy number variants were detected in 7% to 17% of patients with CP in several recent small studies …”

“…Pathogenic de novo copy number variants were detected in 7% to 17% of patients with CP in several recent small studies. [25][26][27] Tests based on NGS techniques, including multigene panels and when accessible, whole-exome and -genome sequencing (WES and WGS) may be pursued if the diagnosis remains uncertain. When the syndrome is clinically or radiologically distinct (e.g., hereditary spastic paraplegia or leukodystrophy), it may be appropriate to perform a targeted, multigene panel first.…”

Measuring “Intolerance to Mutation” in Human Genetics

“…The pLI measure has been broadly applied in human genetics to help identify genes in which a single disrupting mutation is likely of clinical significance 4,[38][39][40][41][42][43][44][45] . pLI is also increasingly used in clinical annotation and in databases of mouse models as indicative of haploinsufficiency and dosage sensitivity [46][47][48][49][50] .…”