Genetic Study of Khyber-Pukhtunkhwa Resident Pakistani Families Presenting Primary Microcephaly With Intellectual Disability

Ahmed, Jamshaid; Windpassinger, Christian; Salim, Muhammad; Wiener, Magdalena; Petek, Erwin; Schaflinger, Erich; Taj, Sundus; Hussain, Saddam; Abbas, Safdar; Abbas, Muhammad; Younis, Itezaz; Muhammad, Noor; Khan, Saadullah; Ahmad, Jamshed

doi:10.5455/jpma.300681

Cited by 6 publications

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“…ASPM mutations do not show great clinical heterogeneity or strong genotype-phenotype correlation. 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 …”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

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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“…Previously published old demographic studies have shown that the incidence of MCPH occurs one in a million in the Yorkshire region of Britain, 1/250,000 in Holland, 1/30,000 in Japan, and 1/2000,000 in Scotland 4–6 . Nevertheless, its incidence rate is believed to be greater in a consanguineous society of Pakistan, Iran, and Arab 7 . Radiologic studies have shown that microcephalic patients have no gross abnormality in brain morphology, except a small volume of the cerebral cortex.…”

Section: Introductionmentioning

confidence: 99%

“…[4][5][6] Nevertheless, its incidence rate is believed to be greater in a consanguineous society of Pakistan, Iran, and Arab. 7 Radiologic studies have shown that microcephalic patients have no gross abnormality in brain morphology, except a small volume of the cerebral cortex. The MCPH patients also exhibit a variable degree of intellectual disability.…”

Section: Introductionmentioning

confidence: 99%

Mutation screening of multiple Pakistani MCPH families revealed novel and recurrent protein‐truncating mutations of ASPM

Hussain

Nawaz

Hamid

et al. 2021

Biotech and App Biochem

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Autosomal primary microcephaly (MCPH) is a heterogenetic disorder that affects brain's cerebral cortex size and leads to a reduction in the cranial vault. Along with the hallmark feature of reduced head circumference, microcephalic patients also exhibit a variable degree of intellectual disability as well. Genetic studies have reported 28 MCPH genes, most of which produce microtubuleassociated proteins and are involved in cell division. Herein this study, 14 patients from seven Pashtun origin Pakistani families of primary microcephaly were analyzed. Mutation analysis was performed through targeted Sanger DNA sequencing on the basis of phenotype-linked genetic makeup. Genetic analysis in one family found a novel pathogenic DNA change in the abnormal spindle microtubule assembly (ASPM) gene (NM_018136.4:c.3871dupGA), while the rest of the families revealed recurrent nonsense mutation c.3978G>A (p.Trp1326*) in the same gene. The novel reported frameshift insertion presumably truncates the protein p.(Lys1291Glyfs*14) and deletes the N-terminus domains. Identification of novel ASPM-truncating mutation expands the mutational spectrum of the ASPM gene, while mapping of recurrent mutation c.3978G>A (p.Trp1326*) will aid in establishing its founder effect in the Khyber Pakhtunkhwa (KPK) inhabitant population of Pakistan and should be suggestively screened for premarital counseling of MCPH susceptible families. Most of the recruited families are related to first-degree consanguinity. Hence, all the family elders were counseled to avoid intrafamilial marriages.

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“…This study, thus, further endorses ASPM mutations as the most frequent cause of microcephaly. The p.Trp1326 * variant has been previously reported as a founder mutation in more than 50 families among various Pashtun tribes including Wazir ( 4 , 12 ). The segregation of this variant in 10 unrelated Wazir families in the current study suggests that this variant represents an old mutation and that mutations in this gene are a rare event.…”

Section: Introductionmentioning

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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Genetic Study of Khyber-Pukhtunkhwa Resident Pakistani Families Presenting Primary Microcephaly With Intellectual Disability

Cited by 6 publications

References 0 publications

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

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

Mutation screening of multiple Pakistani MCPH families revealed novel and recurrent protein‐truncating mutations of ASPM

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

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