Genetic heterogeneity in Pakistani microcephaly families

Hussain, Muhammad Sajid; Bakhtiar, Syeda Marriam; Farooq, Muhammad; Anjum, Iram; Janzen, Eva; Toliat, Mohammad Reza; Eiberg, Hans; Kjær, Kirsten; Tommerup, Niels; Noegel, AA; Nürnberg, Peter; Sm, Baig; Hansen, Lars

doi:10.1111/j.1399-0004.2012.01932.x

Cited by 45 publications

(40 citation statements)

References 16 publications

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“…In both of the current families, patients had normal height and weight and no phenotypic resemblance to PCC syndrome was observed. To date a total of 18 MCPH1 mutations have been reported and only 2 of them in the Pakistani population . This work adds two further MCPH1 mutations from the Pakistani population, thereby increasing the total number of MCPH1 mutations to 20.…”

Section: Discussionmentioning

confidence: 99%

Genetic heterogeneity in Pakistani microcephaly families revisited

et al. 2017

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Autosomal recessive primary microcephaly (MCPH) is a rare and heterogeneous genetic disorder characterized by reduced head circumference, low cognitive prowess and, in general, architecturally normal brains. As many as 14 different loci have already been mapped. We recruited 35 MCPH families in Pakistan and could identify the genetic cause of the disease in 31 of them. Using homozygosity mapping complemented with whole-exome, gene panel or Sanger sequencing, we identified 12 novel mutations in 3 known MCPH-associated genes - 9 in ASPM, 2 in MCPH1 and 1 in CDK5RAP2. The 2 MCPH1 mutations were homozygous microdeletions of 164,250 and 577,594 bp, respectively, for which we were able to map the exact breakpoints. We also identified four known mutations - three in ASPM and one in WDR62. The latter was initially deemed to be a missense mutation but we demonstrate here that it affects splicing. As to ASPM, as many as 17 out of 27 MCPH5 families that we ascertained in our sample were found to carry the previously reported founder mutation p.Trp1326*. This study adds to the mutational spectra of four known MCPH-associated genes and updates our knowledge about the genetic heterogeneity of MCPH in the Pakistani population considering its ethnic diversity.

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Section: Discussionmentioning

confidence: 99%

Genetic heterogeneity in Pakistani microcephaly families revisited

et al. 2017

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“…Most of these genes have been well-established as genes involved in ARID with or without micro-cephaly. In Pakistan, ASPM and WDR62 variants are the most common genetic causes of ARID with microcephaly (Sajid Hussain et al 2013). In this study, of the eight families with ARID and microcephaly, four families have variants in either ASPM or WDR62 (Table 3).…”

Section: Discussionmentioning

confidence: 99%

Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability

Santos‐Cortez

Khan

et al. 2018

Hum Genet

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Identification of Mendelian genes for neurodevelopmental disorders using exome sequencing to study autosomal recessive (AR) consanguineous pedigrees has been highly successful. To identify causal variants for syndromic and non-syndromic intellectual disability (ID), exome sequencing was performed using DNA samples from 22 consanguineous Pakistani families with ARID, of which 21 have additional phenotypes including microcephaly. To aid in variant identification, homozygosity mapping and linkage analysis were performed. DNA samples from affected family member(s) from every pedigree underwent exome sequencing. Identified rare damaging exome variants were tested for co-segregation with ID using Sanger sequencing. For seven ARID families, variants were identified in genes not previously associated with ID, including: EI24, FXR1 and TET3 for which knockout mouse models have brain defects; and CACNG7 and TRAPPC10 where cell studies suggest roles in important neural pathways. For two families, the novel ARID genes CARNMT1 and GARNL3 lie within previously reported ID microdeletion regions. We also observed homozygous variants in two ID candidate genes, GRAMD1B and TBRG1, for which each has been previously reported in a single family. An additional 14 families have homozygous variants in established ID genes, of which 11 variants are novel. All ARID genes have increased expression in specific structures of the developing and adult human brain and 91% of the genes are differentially expressed in utero or during early childhood. The identification of novel ARID candidate genes and variants adds to the knowledge base that is required to further understand human brain function and development.

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“…Clinical features of MCPH2 include epilepsy, marked cognitive impairment, incontinence, sloping forehead and prominent ears. Radiological features are variable and may include polymicrogyria, corpus callosum hypoplasia, heterotopias, pachygyria with cortical thickening, lissencephaly and schizencephaly, although patients can present with isolated microcephaly [14-18]. To date, 34 families have been identified with mutations in WDR62 , the reported affected individuals ranging in age from infancy to mid-teens [14-18].…”

Section: Discussionmentioning

confidence: 99%

“…Radiological features are variable and may include polymicrogyria, corpus callosum hypoplasia, heterotopias, pachygyria with cortical thickening, lissencephaly and schizencephaly, although patients can present with isolated microcephaly [14-18]. To date, 34 families have been identified with mutations in WDR62 , the reported affected individuals ranging in age from infancy to mid-teens [14-18]. We present here the oldest patients known to have WDR62 mutations associated with MCPH, providing additional insight into the natural history and phenotypic spectrum of this disorder.…”

Section: Discussionmentioning

confidence: 99%

The utility of exome sequencing for genetic diagnosis in a familial microcephaly epilepsy syndrome

et al. 2014

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BackgroundDespite remarkable advances in genetic testing, many adults with syndromic epilepsy remain without a molecular diagnosis. The challenge in providing genetic testing for this patient population lies in the extensive genetic heterogeneity associated with epilepsy. Even for the subset of epilepsy patients that present with a defining feature, such as microcephaly, the number of possible genes that would require interrogation by Sanger sequencing is extensive and often prohibitively expensive.Case presentationWe report a family of French Canadian descent with four adult children affected with severe intellectual disability, epilepsy and microcephaly born to consanguineous parents and evaluated by the Genetics Service to provide informed genetic counseling to unaffected family members regarding possible recurrence risks. We used whole-exome sequencing (WES) of DNA from one affected sibling as a first-line diagnostic tool and compared the prioritization of variants using two strategies: 1) focusing on genes with homozygous variants; and, 2) focusing on genes associated with microcephaly. Both approaches prioritized the same homozygous novel frameshift mutation (p.Arg608Serfs*26) in WDR62, a gene known to cause autosomal recessive primary microcephaly. Sanger sequencing confirmed the presence of the homozygous mutation in the other three affected siblings.ConclusionsWES and subsequent filtering of the rare variants in a single affected family member led to the rapid and cost-effective identification of a novel homozygous frameshift mutation in WDR62, thereby explaining the severe neurodevelopmental disorder in this family and facilitating genetic counseling. Our findings support WES as an effective first-line diagnostic tool in families presenting with rare genetically heterogeneous neurological disorders.

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Genetic heterogeneity in Pakistani microcephaly families

Cited by 45 publications

References 16 publications

Genetic heterogeneity in Pakistani microcephaly families revisited

Genetic heterogeneity in Pakistani microcephaly families revisited

Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability

The utility of exome sequencing for genetic diagnosis in a familial microcephaly epilepsy syndrome

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