Whole exome sequencing identifies a novel homozygous frameshift mutation in the ASPM gene, which causes microcephaly 5, primary, autosomal recessive.

Desaraju Suresh Bhargav,Srinivas Kovvali,Soumya Vivek,N Sreedevi,N Swapna

doi:10.12688/f1000research.12102.1

Desaraju Suresh Bhargav, Srinivas Kovvali + Show 3 more

Open Access

https://doi.org/10.12688/f1000research.12102.1

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Abstract

Microcephaly is a genetically heterogeneous disorder and is one of the frequently notable conditions in paediatric neuropathology which exists either as a single entity or in association with other co-morbidities. More than a single gene is implicated in true microcephaly and the list is growing with the recent advancements in sequencing technologies. Using massive parallel sequencing, we identified a novel frame shift insertion in the abnormal spindle-like microcephaly-associated protein gene in a client with true autosomal recessive primary microcephaly. Exome sequencing in the present case helped in identifying the true cause behind the disease, which helps in the premarital counselling for the sibling to avoid future recurrence of the disorder in the family.

Highlights

With no other anomalies in the brain structure is termed as true microcephaly or autosomal recessive primary microcephaly (MCPH), where the pathology of brain is generally congenital and static with mild to moderate intellectual disability (ID)
Using whole exome sequencing (WES), we report a de novo frame shift mutation in the calponin-homology domain of ASPM (Abnormal Spindle-Like, Microcephaly-Associated) gene which is a candidate for MCPH5 (Microcephaly 5, primary, autosomal recessive) in a client with true microcephaly
The novel insertion mutation found in the ASPM gene in the present study segregated with the phenotype in the family, establishes the role of the novel frame shift mutation identifiedin the development of MCPH5 in the case studied

Summary

Introduction

With no other anomalies in the brain structure is termed as true microcephaly or autosomal recessive primary microcephaly (MCPH), where the pathology of brain is generally congenital and static with mild to moderate intellectual disability (ID) (http://www.orpha.net/consor/cgi-bin/OC_Exp. php?Expert=2512). Report The client sequenced was under the research project cerebral palsy and spectrum conditions (seizures, mental retardation, microcephaly and other neurodevelopmental disorders), which aims to find disease causing mutations in a sample of 100 clients recruited from our Motor Speech Disorders Clinic at Department of Clinical Services, All India Institute of Speech and Hearing. At age 12 years, her developmental age was between 66 to 78 months as assessed by the Developmental Screening Test (DST)[4] Her Receptive Language Age (RLA) and Expressive Language Age (ELA) was 18–20 months as revealed by Receptive Expressive Emergent Language Scale (REELS)[5]. She had a vocabulary of around 50 words and was able to comprehend commands, would recognize family members and common objects. She expressed herself through single word utterances, gestures and pointing

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