Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.
Animals
CRISPR-Cas Systems
/ genetics
Cilia
/ genetics
Ciliopathies
/ complications
Congenital Abnormalities
/ genetics
Craniofacial Abnormalities
/ complications
Exome
/ genetics
Female
Heart Defects, Congenital
/ complications
Homozygote
Humans
Loss of Function Mutation
/ genetics
Male
Neurodevelopmental Disorders
/ complications
Pedigree
Phenotype
Exome Sequencing
Zebrafish
/ genetics
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
03 06 2020
03 06 2020
Historique:
received:
10
02
2020
revised:
22
03
2020
accepted:
09
04
2020
pubmed:
21
4
2020
medline:
13
8
2021
entrez:
21
4
2020
Statut:
ppublish
Résumé
Despite the wide use of genomics to investigate the molecular basis of rare congenital malformations, a significant fraction of patients remains bereft of diagnosis. As part of our continuous effort to recruit and perform genomic and functional studies on such cohorts, we investigated the genetic and mechanistic cause of disease in two independent consanguineous families affected by overlapping craniofacial, cardiac, laterality and neurodevelopmental anomalies. Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants in three affected individuals. Functional analysis in a zebrafish model revealed that ccdc32 depletion recapitulates the human phenotypes. Because some of the patient phenotypes overlap defects common to ciliopathies, we asked if loss of CCDC32 might contribute to the dysfunction of this organelle. Consistent with this hypothesis, we show that ccdc32 is required for normal cilia formation in zebrafish embryos and mammalian cell culture, arguing that ciliary defects are at least partially involved in the pathomechanism of this disorder.
Identifiants
pubmed: 32307552
pii: 5822585
doi: 10.1093/hmg/ddaa073
pmc: PMC7268788
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1489-1497Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK072301
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM121317
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD042601
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK108738
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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