Prenatal Identification of a Novel Mutation in the MCPH1 Gene Associated with Autosomal Recessive Primary Microcephaly (MCPH) Using Next Generation Sequencing (NGS): A Case Report and Review of the Literature

Abstract

Background: MCPH1 is known as the microcephalin gene (OMIM: *607117), of which the encoding protein is a basic regulator of chromosome condensation (BCRT-BRCA1 C-terminus). The microcephalin protein is made up of three BCRT domains and conserved tandem repeats of interacting phospho-peptides. There is a strong connection between mutations of the MCPH1 gene and reduced brain growth. Specifically, individuals with such mutations have underdeveloped brains, varying levels of mental retardation, delayed speech and poor language skills. Methods: In this article, a family with two affected fetuses presenting a mutation of the MCPH1 gene is reported. During the first trimester ultrasound of the second pregnancy, the measure of nuchal translucency was increased (NT = 3.1 mm) and, therefore, the risk for chromosomal abnormalities was high. Chorionic villi sampling (CVS) was then performed. Afterwards, fetal karyotyping and Next Generation Sequencing were carried out. Afterwards, NGS was also performed in a preserved sample of the first fetus which was terminated due to microcephaly. Results: In this case, the fetuses had a novel homozygous mutation of the MCPH1 gene (c.348del). Their parents were heterozygous for the mutation. The fetuses showed severe microcephaly. Because of the splice sites in introns, this mutation causes the forming of dysfunctional proteins which lack crucial domains of the C-terminus. Conclusion: Our findings portray an association between the new MCPH1 mutation (c.348del) and the clinical features of autosomal recessive primary microcephaly (MCPH), contributing to a broader spectrum related to these pathologies. To our knowledge, this is the first prenatal diagnosis of MCPH due to a novel MCPH1 mutation.

Functional analysis of a novel intronic variant of MCPH1 with autosomal recessive primary microcephaly

“…But Naseer [ 13 ] reported that two new variants of the MCPH1 gene (c.982G > A and c.1273T > A) were discovered in individuals with microcephaly in exon 8. Papoulidis [ 14 ] observed two sequential pregnancies that were complicated by extreme microcephaly due to a homozygous mutation of the MCPH1 gene which were c.348del heterozygous from parents. The phenylalanine amino acid at position 116 of the protein is replaced by the leucine amino acid due to this mutation, which changes the reading frame and leads to an early stop codon at position 145 of the protein.…”

DNA damage and repair: underlying mechanisms leading to microcephaly

“…In contrast, mental disabilities and mild microcephaly are seen in the case of larger mutations affecting the six exons of MCPH1 ( Trimborn et al, 2005 ; Garshasbi et al, 2006 ; Mahmood et al, 2011 ). Individuals presenting mutations in the MCPH1 gene have a head circumference below the mean, mental disabilities, developmental delays, impaired language skills and infertility, and premature chromosome condensation is considered a hallmark of this disease ( Alderton et al, 2006 ; Wood et al, 2007 ; Gruber et al, 2011 ; Liu et al, 2021 ; Papoulidis et al, 2022 ). Mutations in MCPH1 are proposed to link impaired DDR and MCPH occurrence ( Mahmood et al, 2011 ).…”

“…When the head circumference is more than three standard deviations below the mean, it is considered a severe microcephaly ( DeSilva et al, 2017 ; Becerra-Solano et al, 2021 ). This disease can be classified as ( Tubbs and Nussenzweig, 2017 ) primary microcephaly that can be diagnosed right after birth and has a non-progressive nature, or ( Mikolaskova et al, 2018 ) secondary microcephaly that develops at later life stages and is a progressive neurodegenerative disorder ( Papoulidis et al, 2022 ).…”

Genetic susceptibility of vitamin D receptor gene polymorphisms on autosomal recessive primary microcephaly patients in Pakistani population: a case-control and in-silico study

“…Autosomal recessive primary microcephaly (MCPH) is a neurodevelopment condition in which the affected born with less than 3 standard deviation (SD) smaller head circumference (HC) than expected compared to other infants of the same gestational age, sex, and ethnic background [1]. MCPH is a complex neurodevelopmental condition and associated with mild to moderate mental retardation and no obvious structural abnormalities in the brain [2]. The rate of occurrence of primary microcephaly is about 1 in 10,000 in consanguineous population e.g.…”