Whole Exome Sequencing Identifies Three Novel Mutations in the ASPM Gene From Saudi Families Leading to Primary Microcephaly

Naseer, Muhammad Imran; Abdulkareem, Angham Abdulrahman; Muthaffar, Osama; Sogaty, Sameera; Alkhatabi, Hiba; Almaghrabi, Sarah; Chaudhary, Adeel G.

doi:10.3389/fped.2020.627122

Cited by 19 publications

(18 citation statements)

References 29 publications

(31 reference statements)

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“…The high frequency (10 out of 10 Pashtun families) of the ASPM mutation p.Trp1326 * among Pashtun families hints on its role as a founder mutation among Pashtuns, especially the Wazir tribe, of Pakistan and Afghanistan. Therefore, testing for this mutation, among Pashtuns, as a first step will be a cost-effective and time-saving approach in the future while performing genetic analysis of MCPH families from this and other populations ( 20 ). Similarly, testing for this mutation can also help in population-wide screening for carrier screening and prenatal diagnosis to prevent further affected births.…”

Section: Discussionmentioning

confidence: 99%

Updates on Clinical and Genetic Heterogeneity of ASPM in 12 Autosomal Recessive Primary Microcephaly Families in Pakistani Population

et al. 2021

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Microcephaly (MCPH) is a genetically heterogeneous disorder characterized by non-progressive intellectual disability, small head circumference, and small brain size compared with the age- and sex-matched population. MCPH manifests as an isolated condition or part of another clinical syndrome; so far, 25 genes have been linked with MCPH. Many of these genes are reported in Pakistani population, but due to a high rate of consanguinity, a significant proportion of MCPH cohort is yet to be explored. MCPH5 is the most frequently reported type, accounting for up to 68.75% alone in a genetically constrained population like Pakistan. In the current study, whole exome sequencing (WES) was performed on probands from 10 families sampled from South Waziristan and two families from rural areas of the Pakistani Punjab. Candidate variants were validated through Sanger sequencing in all available family members. Variant filtering and in silico analysis identified three known mutations in ASPM, a MCPH5-associated gene. The founder mutation p.Trp1326* was segregating in 10 families, which further confirmed the evidence that it is the most prominent mutation in Pashtun ethnicity living in Pakistan and Afghanistan. Furthermore, the previously known mutations p.Arg3244* and p.Arg1019* were inherited in two families with Punjab ethnic profile. Collectively, this study added 12 more families to the mutational paradigm of ASPM and expanded the Pakistani MCPH cohort.

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Section: Discussionmentioning

confidence: 99%

Updates on Clinical and Genetic Heterogeneity of ASPM in 12 Autosomal Recessive Primary Microcephaly Families in Pakistani Population

et al. 2021

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“…16,17 The clinical symptoms of our patients are in line with previous reports of ASPM related microcephaly presenting moderate ID, speech impairment, visual abnormalities, seizures, and ptyalism. 4,15,18,19 The mutation CDK5RAP2: c.448C>T p. (Arg150*) segregating in family B is predicted to cause very early termination of the translation. The mutant transcript is predicted to undergo NMD and thus produce no protein.…”

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing identifies a novel mutation in ASPM and ultra-rare mutation in CDK5RAP2 causing Primary microcephaly in consanguineous Pakistani families

et al. 2021

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Background & Objectives: Primary Microcephaly (MCPH) is a rare neurogenetic disease, manifesting congenitally reduced head circumference and non-progressive intellectual disability (ID). To date, twenty-eight genes with biallelic mutations have been reported for this disorder. The study aimed for molecular genetic characterization of Pakistani families segregating MCPH. Methods: We studied two unrelated consanguineous families (family A and B) presenting >2 patients with diagnostic symptoms of MCPH, born to asymptomatic parents. We employed whole-exome sequencing (WES) of probands to find putative causal mutations. The candidate variants were further confirmed and analyzed for co-segregation by Sanger sequencing of all available members of each family. This study was conducted at Government College University, Faisalabad, Pakistan, and Cologne Center for Genomics (CCG), University of Cologne, Germany; during 2017-2020. Results: We identified a novel homozygous variant c.10097_10098delGA, p.(Gly3366Glufs*19) in exon 26 of ASPM gene in family A which presents with moderate intellectual disability, speech impairment, visual abnormalities, seizures, and ptyalism. Family B was found to segregate nonsense, homozygous variant c.448C>T p.(Arg150*) in CDK5RAP2. The patients also exhibited mild to severe seizures without ptyalism that has not been previously reported in patients with mutations in the CDK5RAP2 gene. Conclusion: We report a novel mutation in ASPM and ultra-rare mutation in the CDK5RAP2 gene, both causing primary microcephaly. The study expands the mutational spectrum of the ASPM gene to 212, and also adds to the clinical spectrum of CDK5RAP2 mutations. It also demonstrated the utility of WES in the investigation and genetic diagnosis of genetically heterogeneous disorders like MCPH. These findings would aid in diagnostic and preventive strategies including carrier screening, cascade testing, and genetic counselling. doi: https://doi.org/10.12669/pjms.38.1.4464 How to cite this:Makhdoom EH, Anwar H, Baig SM, Hussain G. Whole exome sequencing identifies a novel mutation in ASPM and ultra-rare mutation in CDK5RAP2 causing Primary microcephaly in consanguineous Pakistani families. Pak J Med Sci. 2022;38(1):---------. doi: https://doi.org/10.12669/pjms.38.1.4464 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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“…Missense (n=22) variations were common among the disease variations in the patients with neurogenetic disorders (Figure 3) [40]. RTTN and ASPM genes were associated with primary microcephaly apart from the above listed [40][41][42], Cerebellar ataxia in sibling WES study showed novel variant in CWF19L1 gene [43] and GBA2 gene in consanguineous Saudi family [44]. A study from Qatari subject revealed the association of novel pathogenic PGAP3 variant with global developmental delay and neuromuscular abnormalities and brain anomalies [45].…”

Section: Neurogenetic Disorders and Candidate Genesmentioning

confidence: 98%

“…Protein-protein interaction analysis of genes of intellectual disability candidate genes of Arab population. P r e p r i n t Powered by TCPDF (www.tcpdf.org) P r e p r i n t Powered by TCPDF (www.tcpdf.org) P r e p r i n t Powered by TCPDF (www.tcpdf.org) Powered by TCPDF (www.tcpdf.org) Protein-protein interaction analysis of C12orf57 gene with literature using STRING [42]. C: Protein-protein interaction analysis of genes of intellectual disability candidate genes of Arab population.…”

Section: Legendmentioning

confidence: 99%

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Heterogeneity in biomarkers, mitogenome and genetic disorders of Arab population with special emphasis on large-scale whole-exome sequencing

Borgio

2021

Arch Med Sci

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More than 25 million DNA variations were discovered as novel including major alleles from Arab population. Exome studies on Arabs discovered >3000 novel nucleotide variants associated with >1200 rare genetic disorders. Reclassification of many pathogenic variant into benign through the Arab database enhance building a detailed and comprehensive map of Arab morbid genome. Intellectual disability stands first with the combined and observed carrier frequency. Genome studies and advanced computational biology discovered interesting novel candidate disease marker variations in many genes from consanguineous families with intellectual disability, neurogenetic disorders, blood and bleeding disorder and rare genetic diseases. Pathogenic variants in C12orf57 gene are prominently associated with the etiology of developmental delay/intellectual impairment. Arab mitogenome exposed hundreds of variations in mtDNA genome and its association with obesity. Further study is needed in genomics to fully comprehend the molecular abnormalities and associated pathogenesis that cause inherited disorders in Arab ancestries.

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Whole Exome Sequencing Identifies Three Novel Mutations in the ASPM Gene From Saudi Families Leading to Primary Microcephaly

Cited by 19 publications

References 29 publications

Updates on Clinical and Genetic Heterogeneity of ASPM in 12 Autosomal Recessive Primary Microcephaly Families in Pakistani Population

Updates on Clinical and Genetic Heterogeneity of ASPM in 12 Autosomal Recessive Primary Microcephaly Families in Pakistani Population

Whole exome sequencing identifies a novel mutation in ASPM and ultra-rare mutation in CDK5RAP2 causing Primary microcephaly in consanguineous Pakistani families

Heterogeneity in biomarkers, mitogenome and genetic disorders of Arab population with special emphasis on large-scale whole-exome sequencing

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