Exome sequencing identifies novel and known mutations in families with intellectual disability

Abstract Background Intellectual disability (ID) is a phenotypically and genetically heterogeneous disorder. Methods In this study, genome wide SNP microarray and whole exome sequencing are used for the variant identification in eight Pakistani families with ID. Beside ID, most of the affected individuals had speech delay, facial dysmorphism and impaired cognitive abilities. Repetitive behavior was observed in MRID143, while seizures were reported in affected individuals belonging to MRID137 and MRID175. Results In two families (MRID137b and MRID175), we identified variants in the genes CCS and ELFN1, which have not previously been reported to cause ID. In four families, variants were identified in ARX, C5orf42, GNE and METTL4. A copy number variation (CNV) was identified in IL1RAPL1 gene in MRID165. Conclusion These findings expand the existing knowledge of variants and genes implicated in autosomal recessive and X linked ID.

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

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.38.1.4464 ◽

2021 ◽

Vol 38 (1) ◽

Author(s):

Ehtisham ul Haq Makhdoom ◽

Haseeb Anwar ◽

Shahid Mahmood Baig ◽

Ghulam Hussain

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Novel Mutation ◽

Speech Impairment ◽

Primary Microcephaly ◽

Rare Mutation ◽

Homozygous Variant ◽

Whole Exome ◽

Pakistani Families

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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Whole-exome sequencing identifies a novel mutation in spermine synthase gene (SMS) associated with Snyder-Robinson Syndrome

10.21203/rs.3.rs-23574/v4 ◽

2020 ◽

Author(s):

Talal J. Qazi ◽

Qiao Wu ◽

Ailikemu Aierken ◽

Daru Lu ◽

Ihtisham Bukhari ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Mutational Analysis ◽

Novel Mutation ◽

Pathogenic Variant ◽

Facial Dysmorphism ◽

Pakistani Family ◽

Spermine Synthase ◽

Whole Exome

Abstract Background: Loss of function mutations in the spermine synthase gene (SMS) have been reported to cause a rare X-linked intellectual disability known as Snyder-Robinson Syndrome (SRS). Besides intellectual disability, SRS is also characterized by reduced bone density, osteoporosis and facial dysmorphism. SRS phenotypes evolve with age from childhood to adulthood. Methods: Whole exome sequencing was performed to know the causative gene/pathogenic variant. Later we confirmed the pathogenic variant through Sanger sequencing. Furthermore, we also performed the mutational analysis through HOPE SERVER and SWISS-MODEL. Also, radiographs were also obtained for affected individual to confirm the disease features. Results: In this article, we report the first Pakistani family consisting of three patients with SRS and a novel missense pathogenic variant in the SMS gene (c.905 C>T p.(Ser302Leu)). In addition to the typical phenotypes, one patient presented with early-onset seizures. Clinical features, genetic and in-silico analysis linked the affected patients of the family with Snyder-Robinson and suggest that this novel mutation affects the spermine synthase activity Conclusion: A novel missense variant in the SMS, c.905C >T p. (Ser302Leu), causing Snyder- Robinson Syndrome (SRS) is reported in three members of Pakistani Family.

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Whole exome sequencing identifies a novel mutation in spermine synthase gene (SMS) associated with Snyder-Robinson Syndrome

10.21203/rs.3.rs-23574/v3 ◽

2020 ◽

Author(s):

Talal J. Qazi ◽

Qiao Wu ◽

Ailikemu Aierken ◽

Daru Lu ◽

Ihtisham Bukhari ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Mutational Analysis ◽

Novel Mutation ◽

Pathogenic Variant ◽

Facial Dysmorphism ◽

Pakistani Family ◽

Spermine Synthase ◽

Whole Exome

Abstract Background: Loss of function mutations in the spermine synthase gene (SMS) have been reported to cause a rare X-linked intellectual disability known as Snyder-Robinson Syndrome (SRS). Besides intellectual disability, SRS is also characterized by reduced bone density, osteoporosis and facial dysmorphism. SRS phenotypes evolve with age from childhood to adulthood. Methods: Whole exome sequencing was performed to know the causative gene/pathogenic variant. Later we confirmed the pathogenic variant through Sanger sequencing. Furthermore, we also performed the mutational analysis through HOPE SERVER and SWISS-MODEL. Also, radiographs were also obtained for affected individual to confirm the disease features. Results: In this article, we report the first Pakistani family consisting of three patients with SRS and a novel missense pathogenic variant in the SMS gene (c.905 C>T p.(Ser302Leu)). In addition to the typical phenotypes, one patient presented with early-onset seizures. Clinical features, genetic and in-silico analysis linked the affected patients of the family with Snyder-Robinson and suggest that this novel mutation affects the spermine synthase activityConclusion: A novel missense variant in the SMS, c.905C >T p. (Ser302Leu), causing Snyder- Robinson Syndrome (SRS) is reported in three members of Pakistani Family.

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Whole exome sequencing identifies a novel mutation in spermine synthase gene (SMS) associated with Snyder-Robinson Syndrome

10.21203/rs.3.rs-23574/v2 ◽

2020 ◽

Author(s):

Talal J. Qazi ◽

Qiao Wu ◽

Ailikemu Aierken ◽

Daru Lu ◽

Ihtisham Bukhari ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Mutational Analysis ◽

Novel Mutation ◽

Pathogenic Variant ◽

Facial Dysmorphism ◽

Pakistani Family ◽

Spermine Synthase ◽

Whole Exome

Abstract Background: Loss of function mutations in the spermine synthase gene (SMS) have been reported to cause a rare X-linked intellectual disability known as Snyder-Robinson Syndrome (SRS). Besides intellectual disability, SRS is also characterized by reduced bone density, osteoporosis and facial dysmorphism. SRS phenotypes evolve with age from childhood to adulthood. Methods: Whole exome sequencing was performed to know the causative gene/pathogenic variant. Later we confirmed the pathogenic variant through Sanger sequencing. Furthermore, we also performed the mutational analysis through HOPE SERVER and SWISS-MODEL. Also, radiographs were also obtained for affected individual to confirm the disease features. Results: In this article, we report the first Pakistani family consisting of three patients with SRS and a novel missense pathogenic variant in the SMS gene (c.905 C>T p.(Ser302Leu)). In addition to the typical phenotypes, one patient presented with early-onset seizures. Clinical features, genetic and in-silico analysis linked the affected patients of the family with Snyder-Robinson and suggest that this novel mutation affects the spermine synthase activityConclusion: A novel missense variant in the SMS, c.905C >T p. (Ser302Leu), causing Snyder- Robinson Syndrome (SRS) is reported in three members of Pakistani Family.

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Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis

Human Genetics ◽

10.1007/s00439-013-1296-1 ◽

2013 ◽

Vol 132 (7) ◽

pp. 825-841 ◽

Cited By ~ 18

Author(s):

Carl Friedrich Classen ◽

Vera Riehmer ◽

Christina Landwehr ◽

Anne Kosfeld ◽

Stefanie Heilmann ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Copy Number ◽

Copy Number Analysis ◽

Genome Wide ◽

Whole Exome

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Whole exome sequencing identifies a novel mutation in spermine synthase gene (SMS) associated with Snyder-Robinson Syndrome

10.21203/rs.3.rs-23574/v1 ◽

2020 ◽

Author(s):

Talal J. Qazi ◽

Qiao Wu ◽

Ailikemu Aierken ◽

Daru Lu ◽

Ihtisham Bukhari ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Missense Mutation ◽

Whole Exome Sequencing ◽

Mutational Analysis ◽

Novel Mutation ◽

Facial Dysmorphism ◽

Clinical Genetic ◽

Spermine Synthase ◽

Whole Exome

Abstract Background: Mutations in the spermine synthase (SMS) gene have been reported to cause a rare x-linked intellectual disability known as Snyder-Robinson Syndrome (SRS). Besides intellectual disability, SRS is also characterized by reduced bone density, bone deformities, osteoporosis and facial dysmorphism. SRS phenotypes evolve with age from childhood to adulthood. Methods: Whole exome sequencing was performed to know the causative gene/mutation. Later we confirmed the mutation through sanger sequencing. Furthermore, we also performed the mutational analysis through HOPE SERVER and SWISS-MODEL. Also, radiographs were also obtained for affected individual to confirm the disease features. Results: In this article, we report the first Pakistani family consisting of three patients with SRS and a novel missense mutation in the SMS gene (c.905C >T: p.S302L). In addition to the typical phenotypes, one patient presented with epilepsy from an early age that was characterized by generalized seizures. The clinical, genetic and in-silico analysis, review of the literature links the affected patients of the family with Snyder-Robinson syndrome and mutation affects the spermine synthase activityConclusion: A novel missense mutation in the SMS gene (c.905C >T: p.S302L) causing Snyder-Robinson Syndrome (SRS) reported in Pakistan Family.

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Identification of genetic causes of congenital neurodevelopmental disorders using genome wide molecular technologies

Acta medica Lituanica ◽

10.6001/actamedica.v23i2.3324 ◽

2016 ◽

Vol 23 (2) ◽

pp. 73-85

Author(s):

Eglė Preikšaitienė ◽

Laima Ambrozaitytė ◽

Živilė Maldžienė ◽

Aušra Morkūnienė ◽

Loreta Cimbalistienė ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Single Gene ◽

Genetic Alterations ◽

Sequence Variants ◽

Candidate Sequence ◽

Genetic Causes ◽

Genome Wide ◽

Whole Exome

Background. Intellectual disability affects about 1–2% of the general population worldwide, and this is the leading socio-economic problem of health care. The evaluation of the genetic causes of intellectual disability is challenging because these conditions are genetically heterogeneous with many different genetic alterations resulting in clinically indistinguishable phenotypes. Genome wide molecular technologies are effective in a research setting for establishing the new genetic basis of a disease. We describe the first Lithuanian experience in genome-wide CNV detection and whole exome sequencing, presenting the results obtained in the research project UNIGENE.Materials and methods. The patients with developmental delay/intellectual disability have been investigated (n = 66). Diagnostic screening was performed using array-CGH technology. FISH and real time-PCR were used for the confirmation of gene-dose imbalances and investigation of parental samples. Whole exome sequencing using the next generation high throughput NGS technique was used to sequence the samples of 12 selected families.Results. 14 out of 66 patients had pathogenic copy number variants, and one patient had novel likely pathogenic aberration (microdeletion at 4p15.2). Twelve families have been processed for whole exome sequencing. Two identified sequence variants could be classified as pathogenic (in MECP2, CREBBP genes). The other families had several candidate intellectual disability gene variants that are of unclear clinical significance and must be further investigated for possible effect on the molecular pathways of intellectual disability.Conclusions. The genetic heterogeneity of intellectual disability requires genome wide approaches, including detection of chromosomal aberrations by chromosomal microarrays and whole exome sequencing capable of uncovering single gene mutations. This study demonstrates the benefits and challenges that accompany the use of genome wide molecular technologies and provides genotype-phenotype information on 32 patients with chromosomal imbalances and ID candidate sequence variants.

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Genetic Analysis of Children With Unexplained Developmental Delay and/or Intellectual Disability by Whole-Exome Sequencing

Frontiers in Genetics ◽

10.3389/fgene.2021.738561 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jingjing Xiang ◽

Yang Ding ◽

Fei Yang ◽

Ang Gao ◽

Wei Zhang ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Developmental Delay ◽

Whole Exome Sequencing ◽

Neurodevelopmental Disorders ◽

Copy Number ◽

Diagnostic Yield ◽

Single Nucleotide ◽

Whole Exome ◽

Number Variation

Background: Whole-exome sequencing (WES) has been recommended as a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders (NDDs). We aimed to identify the genetic causes of 17 children with developmental delay (DD) and/or intellectual disability (ID).Methods: WES and exome-based copy number variation (CNV) analysis were performed for 17 patients with unexplained DD/ID.Results: Single-nucleotide variant (SNV)/small insertion or deletion (Indel) analysis and exome-based CNV calling yielded an overall diagnostic rate of 58.8% (10/17), of which diagnostic SNVs/Indels accounted for 41.2% (7/17) and diagnostic CNVs accounted for 17.6% (3/17).Conclusion: Our findings expand the known mutation spectrum of genes related to DD/ID and indicate that exome-based CNV analysis could improve the diagnostic yield of patients with DD/ID.

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