A de novo deletion in a boy with cerebral palsy suggests a refined critical region for the 4q21.22 microdeletion syndrome

Zarrei, Mehdi; Merico, Daniele; Kellam, Barbara; Engchuan, Worrawat; Scriver, Tara; Jokhan, Rikash; Wilson, Michael D.; Parr, Jeremy; Lemire, Edmond G.; Stavropoulos, Dimitri J.; Scherer, Stephen W.

doi:10.1002/ajmg.a.38176

Cited by 9 publications

(3 citation statements)

References 38 publications

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“…A case of 4q21 deletion in Texas also found the above-mentioned consistent PRKG2 and RASGEF1B key genes [9]. Since then [10], the case of a Canadian 18-year-old boy patient has de ned a minimal critical region within the chromosome 4q deletion region, and the data suggest that HNRNPD and HNRNPDL may be the key genes that cause cerebral palsy and myopathy, which is consistent with the ndings of Hu Xuyun. In several cases, PRKG2 was reported as a key gene for language defects in the 4q21 deletion region, which encodes cGMP-dependent protein kinase II (cGKII).…”

Section: Genetic Test Resultssupporting

confidence: 67%

Chromosome 4q deletion syndrome: 4q13.3-q21.23 deletion syndrome with mental retardation, congenital heart disease: a case report and literature review

Wang

Huang²,

Luo³

et al. 2023

Preprint

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Objective. Chromosome 4q deletion syndrome is a rare disease, and the reported genotypes cannot fully explain the clinical manifestations. This article aims to present a case that provides ideas for the clinical diagnosis of similar conditions, by adding new genotypes to the 4q deletion fragment gene pool. Case presentation.A female child aged 7-month and 3-day-old was born after repeated treatments for “cleft palate, atrial septal defect, mixed deafness, corpus callosum developmental malformation” and other diseases. By searching the PubMed, and Web of Science, CNKI, the published literature on chromosome 4 deletion was sorted and analyzed. Whole-genome sequencing,which was diagnosed as 4q13.3-q21.23 deletion syndrome. Conclusion.The diagnosis of congenital heart defects, progressive growth retardation, and mental retardation with multisystem involvement, and deletion of a gene fragment of chromosome 4 became a disorder to be considered in clinical work. Timely analysis of genetic findings could help confirm the diagnosis.

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Section: Genetic Test Resultssupporting

confidence: 67%

Chromosome 4q deletion syndrome: 4q13.3-q21.23 deletion syndrome with mental retardation, congenital heart disease: a case report and literature review

Wang

Huang²,

Luo³

et al. 2023

Preprint

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“…To date, five studies have analyzed genomic copy number variations (CNVs) in CP cases 9,[15][16][17][18] , identifying predicted deleterious CNVs in 10-31% of cases. Three prior whole exome sequencing (WES) studies have been performed in CP cases [19][20][21] .…”

mentioning

confidence: 99%

Mutations disrupting neuritogenesis genes confer risk for cerebral palsy

Jin¹,

Lewis²,

Bakhtiari³

et al. 2020

Nat Genet

129

135

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Cerebral palsy (CP), a neurodevelopmental disorder characterized by irreversible, nonprogressive central motor dysfunction, is commonly associated with prematurity or perinatal brain injury. However, accumulating evidence suggests deleterious genomic variants may contribute to CP in addition to environmental insults. To identify genes contributing to risk for CP, we performed whole-exome sequencing on 250 parent-offspring CP trios. We identified a significant contribution of damaging de novo mutations (DNMs), especially in genes that are intolerant to loss of function mutations. Eight genes had multiple, independently-arising damaging DNMs, including two novel CP-associated genes, FBXO31 and RHOB, and four genes previously implicated in cerebral palsy phenotypes, TUBA1A, CTNNB1, SPAST, and ATL1. Functional experiments, including molecular and biochemical assays and patient fibroblast studies indicate that the recurrent RHOB mutation identified in patients enhances Rho effector binding in the active state and that the FBXO31 mutation leads to elevated levels of cyclin D. Analysis of candidate CP risk genes highlighted genetic overlap with hereditary spastic paraplegia as well as intellectual disability, autism, and epilepsy, converging with epidemiologic findings. Computational network analysis of risk genes identified significant enrichment of Rho GTPase, extracellular matrix, focal adhesions, cytoskeleton, and cell projection pathways. CP risk genes in Rho GTPase, cytoskeleton and cell projection pathways were found to play an important role in neuromotor development via a Drosophila reverse genetics screen. Based on enrichment analysis, we estimate that an excess of damaging de novo and inherited recessive variants collectively account for ~14% of the cases in our cohort, whereas perinatal asphyxia is currently estimated to occur in 8-10% of CP cases. Together, these findings provide evidence for the role of genetically-mediated dysregulation of early brain connectivity in CP.

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“… 4 We also found multiple large chromosomal anomalies and rare inherited variants in CP cases. 4 , 12 …”

Section: Introductionmentioning

confidence: 99%

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

Zarrei

Fehlings

Mawjee

et al. 2018

Genetics in Medicine

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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.

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A de novo deletion in a boy with cerebral palsy suggests a refined critical region for the 4q21.22 microdeletion syndrome

Cited by 9 publications

References 38 publications

Chromosome 4q deletion syndrome: 4q13.3-q21.23 deletion syndrome with mental retardation, congenital heart disease: a case report and literature review

Chromosome 4q deletion syndrome: 4q13.3-q21.23 deletion syndrome with mental retardation, congenital heart disease: a case report and literature review

Mutations disrupting neuritogenesis genes confer risk for cerebral palsy

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

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