Abstract
BackgroundPrimary microcephaly is a disorder of the brain resulting in a reduced head circumference that can come along with intellectual disability but with hardly any other neurological abnormalities.Case presentationIn this study we report on three Pakistani males from a consanguineous family with 2, 4 and 25 years, diagnosed with autosomal recessive primary microcephaly. By genotyping, Sanger sequencing and using bioinformatical approaches the disease causing mutation was identified and evaluated.ConclusionBy using a 250K SNP array, we were able to detect an 11Mb large autozygous region in the MCPH2 locus on chromosome 19q13.12. Sequencing of the associated gene, WDR62, revealed the frameshift causing single base pair duplication, c.2527dupG. This mutation is predicted to affect the structural features of WDR62 which in turn changes the conformation and function of the protein. Aspartic acid (D) at position 843 was found to be conserved among various ortholog species. The present findings will be helpful in genetic diagnosis of patients and future studies of WDR62.
Highlights
Primary microcephaly is a disorder of the brain resulting in a reduced head circumference that can come along with intellectual disability but with hardly any other neurological abnormalities.Case presentation: In this study we report on three Pakistani males from a consanguineous family with 2, 4 and 25 years, diagnosed with autosomal recessive primary microcephaly
13 MCPH loci and their genes (MCPH1, WDR62, CDK5RAP2, CASC5, ASPM, CENPJ, STIL, CEP63, CEP135, CEP152, PHC1, CDK6 and HsSAS-6 respectively) have been mapped and identified, making this disease a genetically heterogeneous disorder, affecting 1 in 10 000 children that result from consanguineous marriages [4,5,6,7,8,9,10,11,12,13,14,15,16,17]
First studies on WDR62 revealed it as a JNK scaffold protein that associates with the two JNK-signalling pathway proteins JNK (c-Jun N-terminal kinase) and MKK7 (MAP kinase kinase 7) and is recruited to stress granulaes upon cellular stress induction [28]
Summary
According to Mahmood et al [19] ASPM (MCPH5 locus) and WDR62 (MCPH2) are the two most common genes for primary microcephaly found mutated in more than 55% of the affected families. 4% of all MCPH cases are only due to mutations in WDR62 [35]. According to Mahmood et al [19] ASPM (MCPH5 locus) and WDR62 (MCPH2) are the two most common genes for primary microcephaly found mutated in more than 55% of the affected families. 4% of all MCPH cases are only due to mutations in WDR62 [35]. Due to the high prevalence of MCPH2 in primary microcephaly cases among consanguineous families more mutations in this gene will probably be revealed in the upcoming years. The high frequency of WDR62 mutations in consanguineous primary microcephaly patients will especially simplify the clinical counseling and diagnostic screening of non-consanguineous primary microcephaly patients. Consent We have obtained the written informed consent from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review from the Editor of this journal
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