A novel splice-site mutation in the ASPM gene underlies autosomal recessive primary microcephaly

Abstract

BACKGROUNDAutosomal recessive primary microcephaly (MCPH) is a clinically and genetically heterogeneous disorder. Patients with MCPH exhibit reduced occipito-frontal head circumference and non-progressive intellectual disability. To date, 17 genes have been known as an underlying cause of MCPH in humans. ASPM (abnormal spindle-like, microcephaly associated) is the most commonly mutated MCPH gene.OBJECTIVEIdentify the genetic defect underlying MCPH in a Saudi family.DESIGNA cross-sectional clinical genetic study of a Saudi family.SETTINGMadinah Maternity and Children Hospital and Centre for Genetics and Inherited Diseases, Taibah University.PATIENTS AND METHODSA molecular analysis was carried out on DNA samples from 10 individuals of a Saudi family segregating MCPH. DNA was isolated from the peripheral blood of 10 individuals, including 2 patients, and whole exome sequencing was performed using the Nextera Rapid Capture kit and NextSeq500 instrument. VariantStudio was used to filter and prioritize variants.MAIN OUTCOME MEASURE(S)Detection of mutation in the ASPM gene in a family segregating autosomal recessive primary microcephaly.RESULTSA novel homozygous splice-site variant (c.3742-1G>C) in the ASPM gene was identified. The variant is predicted to have an effect on splicing. Human Splice Finder, an in silico tool, predicted skipping of exon 16 due to this variant.CONCLUSIONSkipping of exon 16 may change the order and number of IQ motifs in the ASPM protein leading to typical MCPH phenotype.LIMITATIONSSingle family study.

Autosomal recessive primary microcephaly due to ASPM mutations: An update

“…Deafness (one patient (Darvish et al., ), Guillain‐Barré syndrome (one patient (Passemard et al., )), and nystagmus (patient #24.3) have been reported or noticed in the present study. Fatal issues have been reported three times in the literature: one patient died after acute myeloid leukemia (Al‐Gazali & Ali, ) and two children (3 and 9 years old) died without any reported explanation (Abdel‐Hamid et al., ; Hashmi et al., ). The co‐occurrence of two unrelated genetic diseases has been shown in three patients: one with a deletion of the STS gene (Abdel‐Hamid et al., ), one with oculocutaneous albinism (Abdel‐Hamid et al., ), and one with familial retinitis pigmentosa due to CLN3 mutations (patient #21).…”

“…Although a large number of patients with ASPM mutations have been reported (Abdel‐Hamid et al., ; Ahmad et al., ; Akbariazar et al., ; Al‐Gazali & Ali, ; Ariani et al., ; Bond et al., ; Bond et al., ; Darvish et al., ; Desir, Abramowicz, & Tunca, ; Desir, Cassart, David, Van Bogaert, & Abramowicz, ; Gul et al., ; Gul et al., ; Halsall, Nicholas, Thornton, Martin, & Geoffrey Woods, ; Hashmi et al., ; Hu et al., ; Kousar et al., ; Kumar, Blanton, Babu, Markandaya, & Girimaji, ; Muhammad et al., ; Nakamura et al., ; Nicholas et al., ; Papari et al., ; Passemard et al., ; Pichon, Vankerckhove, Bourrouillou, Duprez, & Abramowicz, ; Rump et al., ; Saadi et al., ; Sajid Hussain et al., ; Shen et al., ; Tan et al., ; Wang, Khan, Han, & Zhang, ), their developmental phenotype has been documented only in a minority of cases. However, ID (Passemard et al., ) and epilepsy (Shen et al., ) are the most frequently reported clinical findings in patients with ASPM mutations.…”

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

“…This increase in the human brain size is believed to be one contributing factor for the emergence of higher cognitive function and language ability that are restricted to humans 8 . So far, 17 genes have been reported in which, mutations lead to the development of MCPH 3 , 4 , 9 – 26 . The phenotype(s) arising from pathogenic variants in these 17 genes are each named from MCPH 1 – MCPH 17 (there are 17 genes identified so far that cause autosomal recessive primary microcephaly, MCPH arising from these 17 genes are termed from MCPH 1 to MCPH 17) and the majority of the genetic load in MCPH is contributed by the ASPM gene, making MPCH5 the most prevalent of all the types of MCPH.…”

“…Microcephaly 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 ). Microcephaly is seen in numerous syndromes 1 and even in true microcephaly, there is possibility of more than one gene implicated 2 , 3 , thus screening for a single gene may not be very fruitful in this population. Recently, whole exome sequencing (WES) has emerged as a potential approach to delineate the molecular pathology in the microcephaly population with ID 1 .…”

Whole exome sequencing identification of a novel insertion mutation in the phospholipase C ε‑1 gene in a family with steroid resistant inherited nephrotic syndrome

“…Library preparation and exome enrichment was performed using the Nextra Rapid Capture Exome kit (Illumina, Inc., San Diego, CA, USA), which captured 214,405 exons and splice sites with 98.3% RefSeq coverage. Subsequently, the Illumina NextSeq500 instrument (Illumina, Inc.) was used to produce clusters and DNA sequence reads, as described previously (22).…”