Article

WDR62 missense mutation in a consanguineous family with primary microcephaly

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 03/2012; 158A(3):622-5. DOI: 10.1002/ajmg.a.34417
Source: PubMed

ABSTRACT

We report on a consanguineous couple with two affected sons who presented with primary microcephaly and moderate to severe intellectual disabilities. A SNP array uncovered two overlapping regions of copy-neutral absence of heterozygosity (AOH) in both sibs. This led to sequencing of WDR62, a gene that codes for a spindle pole protein recently identified as a cause of primary microcephaly. A homozygous missense mutation in WDR62, p.E400K, was found in both boys and segregated with the condition in this family. WDR62 is one of seven genes responsible for autosomal recessive primary microcephaly (MCPH), and appears to be one of the most frequently involved in MCPH following ASPM. Studies of ASPM and WDR62 should perhaps be pursued in all cases of primary microcephaly with or without gross brain malformations.

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    • "WDR62 is the second most frequently mutated gene in MCPH, accounting for about 10% of cases [16] [23] [53] [54]. "
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    ABSTRACT: Autosomal recessive primary microcephaly (MCPH) is a rare hereditary neurodevelopmental disorder characterized by a marked reduction in brain size and intellectual disability. MCPH is genetically heterogeneous and can exhibit additional clinical features that overlap with related disorders including Seckel syndrome, Meier-Gorlin syndrome, and microcephalic osteodysplastic dwarfism. In this review, we discuss the key proteins mutated in MCPH. To date, MCPH-causing mutations have been identified in twelve different genes, many of which encode proteins that are involved in cell cycle regulation or are present at the centrosome, an organelle crucial for mitotic spindle assembly and cell division. We highlight recent findings on MCPH proteins with regard to their role in cell cycle progression, centrosome function, and early brain development.
    Full-text · Article · Dec 2014 · BioMed Research International
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    ABSTRACT: Primary autosomal recessive microcephaly is characterized by: occipito-frontal head circumference (OFC) less than 2 SD below the mean for sex, age, and ethnicity at birth and at least -3 SD after age six months; mild to severe cognitive impairment without major motor delay; absence of neurologic signs except mild seizures; associated hyperkinesia; normal facies except for the narrow, sloping forehead that often accompanies reduced cranial size; absence of malformations in other organ systems; and normal growth except for mild shortness of stature (up to -3 SD). Currently seven loci associated with autosomal recessive primary microcephalies are identified and are designated MCPH(microcephaly primary hereditary)1 - MCPH7. The diagnosis of MCPH1 – MCPH7 is based on clinical findings, brain imaging that shows reduced brain volume with grossly normal architecture, family history consistent with autosomal recessive inheritance, and molecular genetic testing when available. For MCPH1 - MCPH7, five genes are known: MCPH1, the gene encoding microcephalin (locus name: MCPH1); CDK5RAP2 (MCPH3); ASPM (MCPH5); CENPJ (MCPH6); and STIL (MCPH7). Two additional loci, MCPH2 and MCPH4, have been mapped, but the associated MCPH-causing gene has not been identified. The only gene for which molecular genetic testing is clinically available is ASPM (MCPH5), which accounts for 37%-54% of MCPH. Treatment of manifestations: supportive therapy involves special education, language therapy, behavioral therapy, occupational therapy, and community services for families. Ritalin® may be helpful in managing hyperkinesia. Seizures are usually responsive to monotherapy with standard antiepileptic drugs (AEDs). Surveillance: neurologic evaluation from birth to adulthood with periodic neuropsychologic evaluation; monitoring closely for manifestations of seizures. Primary autosomal recessive microcephaly types 1-7 are inherited in an autosomal recessive manner. At conception, each child of two carrier parents has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk for MCPH5 caused by ASPM mutations is possible if the ASPM disease-causing mutations in the family are known. For the other types of MCPH, testing is not available in clinical laboratories but may be available through laboratories offering clinical confirmation of mutations.
    No preview · Chapter · Jan 2009
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    ABSTRACT: Autosomal recessive primary microcephaly (MCPH) is a heterogeneous disorder which mainly affects neurodevelopment. Generally, MCPH patients exhibit mild brain structural anomalies and simplified cerebral cortex, but few recently identified genes are associated with severe brain malformations. Here, we report a five generation Pakistani family with three affected individuals presenting primary microcephaly, intellectual disability, schizencephaly and hypoplasia of corpus callosum. The comparison of available clinical information led to candidate gene mapping and sequencing of WD repeat domain 62 (WDR62) gene which is mostly associated with severe brain malformations. A homozygous deletion mutation c.1143delA was detected in exon 9 of WDR62 gene, in all affected individuals, which resulted in frameshift and protein truncation (p.H381PfsX48). This study supports the frequent involvement of WDR62 in patients with gross brain malformations.
    Full-text · Article · Oct 2012 · Molecular Biology Reports
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