Expanding the spectrum of CEP55‐associated disease to viable phenotypes

Homozygosity for nonsense variants in CEP55 has been associated with a lethal condition characterized by multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly (MARCH syndrome) also known as Meckel‐like syndrome. Missense variants in CEP55 have not previous...

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Bibliographic Details
Published in:American journal of medical genetics. Part A 2020-05, Vol.182 (5), p.1201-1208
Main Authors: Barrie, Elizabeth S., Overwater, Eline, Haelst, Mieke M., Motazacker, M. Mahdi, Truxal, Kristen V., Crist, Erin, Mostafavi, Roya, Pivnick, Eniko K., Choudhri, Asim F., Narumanchi, TaraChandra, Castelluccio, Valerie, Walsh, Laurence E., Garganta, Cheryl, Gastier‐Foster, Julie M.
Format: Article
Language:English
Subjects:
Abnormalities, Multiple - epidemiology
Abnormalities, Multiple - genetics
Abnormalities, Multiple - pathology
Adolescent
Adult
Alternative splicing
Cell Cycle Proteins - genetics
CEP55
Cerebellum
Cerebellum - abnormalities
Cerebellum - pathology
Child
Child, Preschool
Dandy-Walker Syndrome - epidemiology
Dandy-Walker Syndrome - genetics
Dandy-Walker Syndrome - pathology
Developmental Disabilities - epidemiology
Developmental Disabilities - genetics
Developmental Disabilities - pathology
Dysplasia
Female
Genetic Predisposition to Disease
Heterozygosity
Homozygote
Humans
Hydranencephaly
Hypoplasia
Infant
Infant, Newborn
Lissencephaly
Male
MARCH syndrome
Meckel‐like syndrome
Microcephaly
Microcephaly - epidemiology
Microcephaly - genetics
Microcephaly - pathology
Microencephaly
Mutation
Mutation, Missense
Nervous System Malformations - epidemiology
Nervous System Malformations - genetics
Nervous System Malformations - pathology
Pancreatic Cyst - epidemiology
Pancreatic Cyst - genetics
Pancreatic Cyst - pathology
Pedigree
Phenotype
Phenotypes
Pregnancy
Syndactyly
Young Adult
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Summary:Homozygosity for nonsense variants in CEP55 has been associated with a lethal condition characterized by multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly (MARCH syndrome) also known as Meckel‐like syndrome. Missense variants in CEP55 have not previously been reported in association with disease. Here we describe seven living individuals from five families with biallelic CEP55 variants. Four unrelated individuals with microcephaly, speech delays, and bilateral toe syndactyly all have a common CEP55 variant c.70G>A p.(Glu24Lys) in trans with nonsense variants. Three siblings are homozygous for a consensus splice site variant near the end of the gene. These affected girls all have severely delayed development, microcephaly, and varying degrees of lissencephaly/pachygyria. Here we compare our seven patients with three previously reported families with a prenatal lethal phenotype (MARCH syndrome/Meckel‐like syndrome) due to homozygous CEP55 nonsense variants. Our series suggests that individuals with compound heterozygosity for nonsense and missense variants in CEP55 have a different viable phenotype. We show that homozygosity for a splice variant near the end of the CEP55 gene is also compatible with life.
ISSN:1552-4825
1552-4833
DOI:10.1002/ajmg.a.61512