A homozygous variant in ARHGAP39 is associated with lethal cerebellar vermis hypoplasia in a consanguineous Saudi family.
Humans
Homozygote
GTPase-Activating Proteins
/ genetics
Saudi Arabia
Male
Female
Consanguinity
Pedigree
Cerebellar Vermis
/ abnormalities
Exome Sequencing
Chromosomes, Human, Pair 8
/ genetics
Mutation, Missense
Phenotype
Infant
Nervous System Malformations
/ genetics
Child, Preschool
Cerebellum
/ abnormalities
Developmental Disabilities
Cerebellar vermis hypoplasia
Homozygosity mapping
Rho GAP
WES analysis
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
25 Oct 2024
25 Oct 2024
Historique:
received:
18
04
2024
accepted:
23
10
2024
medline:
26
10
2024
pubmed:
26
10
2024
entrez:
25
10
2024
Statut:
epublish
Résumé
Cerebellar vermis hypoplasia refers to a varying degree of incomplete development of the cerebellum and vermis. A Saudi family with four affected individuals with cerebellar vermis hypoplasia, facial dysmorphology, visual impairment, skeletal, and cardiac abnormalities was ascertained in this study. Three out of four patients could not survive longer and had died in early infancy. Genetic analysis of the youngest affected was performed by genome-wide homozygosity mapping coupled with whole exome sequencing (WES), followed by Sanger validation. Genome-wide genotyping analysis mapped the phenotype to chromosome 8q24.3. Using an autosomal recessive model, considering deleterious variants with minor allele frequency of less than 0.001 in WES data, a homozygous missense variant (NM_025251.2; ARHGAP39; c.1301G > T; p.Cys434Phe) was selected as a potential candidate for the phenotype. The variant (c.1301G > T) in the ARHGAP39 is in the region of homozygosity on chromosome 8q24.3. ARHGAP39 is a Rho GTPase-activating protein 39 and has been known to regulate apoptosis, cell migration, neurogenesis, and cerebral and hippocampal dendritic spine morphology. Mice homozygous for arhgap39 knockouts have shown premature embryonic lethality. Our findings present the first ever human phenotype associated with ARHGAP39 alteration.
Identifiants
pubmed: 39455833
doi: 10.1038/s41598-024-77541-0
pii: 10.1038/s41598-024-77541-0
doi:
Substances chimiques
GTPase-Activating Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
25291Subventions
Organisme : King Salman Center for Disability Research
ID : KSRG-2022-088
Informations de copyright
© 2024. The Author(s).
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