Phenotypes and genotypes in non-consanguineous and consanguineous primary microcephaly: High incidence of epilepsy.
Mendeliome
brain developmental disorders
consanguinity
epilepsy
primary microcephaly
rare disease
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
revised:
06
05
2021
received:
12
02
2021
accepted:
03
07
2021
pubmed:
18
8
2021
medline:
17
3
2022
entrez:
17
8
2021
Statut:
ppublish
Résumé
Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge. We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a molecular diagnosis in 38 patients. Pathogenic variants in ASPM and WDR62 were the most frequent causes in non-consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in non-consanguineous patients (9%). Our series includes 11 novel pathogenic variants and we identify novel candidate genes including IGF2BP3 and DNAH2. We confirm the progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients with a molecular confirmation of the PM diagnosis, with various degrees of severity and seizure types. Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses, and improve the management of PM patients.
Sections du résumé
BACKGROUND
Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge.
METHODS
We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a molecular diagnosis in 38 patients.
RESULTS
Pathogenic variants in ASPM and WDR62 were the most frequent causes in non-consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in non-consanguineous patients (9%). Our series includes 11 novel pathogenic variants and we identify novel candidate genes including IGF2BP3 and DNAH2. We confirm the progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients with a molecular confirmation of the PM diagnosis, with various degrees of severity and seizure types.
CONCLUSION
Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses, and improve the management of PM patients.
Identifiants
pubmed: 34402213
doi: 10.1002/mgg3.1768
pmc: PMC8457702
doi:
Substances chimiques
ASPM protein, human
0
Cell Cycle Proteins
0
Nerve Tissue Proteins
0
WDR62 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1768Informations de copyright
© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
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