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.

Figure 1

Pedigrees of selected families (cases C, D, and G) with multiple variants.

Figure 2

Critical exons in genes expressed prenatally are significantly impacted by rare CNVs in 16 different brain regions. The P value is corrected using the Benjamini-Hochberg method. AMY, amygdaloid complex; CBC, cerebellar cortex; V1C, primary visual cortex; STC, posterior (caudal) superior temporal cortex; IPC, posterior inferior parietal cortex; A1C, primary auditory cortex; S1C, primary somatosensory cortex; M1C, primary motor cortex; STR, striatum; DFC, dorsolateral prefrontal cortex; MFC, medial prefrontal cortex; VFC, ventrolateral prefrontal cortex; OFC, orbital frontal cortex; MD, mediodorsal nucleus of thalamus; ITC, inferolateral temporal cortex; HIP, hippocampus.