A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

AbstractThe genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line.

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Case report : a novel ASXL3 gene variant in a Sudanese boy

BMC Pediatrics ◽

10.1186/s12887-021-03038-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ke Wu ◽

Yan Cong

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Psychomotor Development ◽

Gene Variant ◽

Feeding Difficulties ◽

Severe Intellectual Disability ◽

Whole Exome

Abstract Background Bainbridge-Ropers syndrome (BRPS) [OMIM#615485] is a neurodevelopmental disorder, characterized by delayed psychomotor development with generalized hypotonia, moderate to severe intellectual disability, poor or absent speech, feeding difficulties, growth failure, dysmorphic craniofacial features and minor skeletal features. The aim of this study was to investigate the genetic etiology of a Sudanese boy with severe developmental delay, intellectual disability, and craniofacial phenotype using trio-based whole-exome sequencing. To our knowledge, no patients with ASXL3 gene variant c.3043C>T have been reported detailedly in literature. Case presentation The patient (male, 3 years 6 months) was the first born of a healthy non-consanguineous couple originating from Sudan, treated for “psychomotor retardation” for more than 8 months in Yiwu. The patient exhibited severely delayed milestones in physiological and intellectual developmental stages, language impairment, poor eye-contact, lack of subtle motions of fingers, fear of claustrophobic space, hypotonia, clinodactyly, autistic features. Peripheral blood samples were collected from the patient and his parents. Trio-based whole-exome sequencing(Trio-WES) identified a de novo heterozygous ASXL3 gene variant c.3043C>T;p.Q1015X. Sanger sequencing verified variants of this family. Conclusion Trio-WES analysis identified a de novo nonsense variant (c.3043C>T) of ASXL3 gene in a Sudanese boy. To our knowledge, the patient with this variant has not been reported previously in literature. This study presents a new case for ASXL3 gene variants, which expanded the mutational and phenotypic spectrum.

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RHOBTB2 p.Arg511Trp Mutation in Early Infantile Epileptic Encephalopathy-64: Review and Case Report

Journal of Pediatric Genetics ◽

10.1055/s-0040-1722288 ◽

2021 ◽

Author(s):

J Fonseca ◽

C Melo ◽

C Ferreira ◽

M Sampaio ◽

R Sousa ◽

...

Keyword(s):

Case Report ◽

Intellectual Disability ◽

Status Epilepticus ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Epileptic Encephalopathy ◽

Btb Domain ◽

Pathogenic Variants ◽

Severe Intellectual Disability ◽

Whole Exome

AbstractEarly infantile epileptic encephalopathy-64 (EIEE 64), also called RHOBTB2-related developmental and epileptic encephalopathy (DEE), is caused by heterozygous pathogenic variants (EIEE 64; MIM#618004) in the Rho-related BTB domain-containing protein 2 (RHOBTB2) gene. To date, only 13 cases with RHOBTB2-related DEE have been reported. We add to the literature the 14th case of EIEE 64, identified by whole exome sequencing, caused by a heterozygous pathogenic variant in RHOBTB2 (c.1531C > T), p.Arg511Trp. This additional case supports the main features of RHOBTB2-related DEE: infantile-onset seizures, severe intellectual disability, impaired motor functions, postnatal microcephaly, recurrent status epilepticus, and hemiparesis after seizures.

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A Novel De Novo Frameshift Mutation in KAT6A Identified by Whole Exome Sequencing

Journal of Pediatric Genetics ◽

10.1055/s-0038-1676649 ◽

2018 ◽

Vol 08 (01) ◽

pp. 010-014 ◽

Cited By ~ 2

Author(s):

Wafa Alazaizeh ◽

Asem Alkhateeb

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Frameshift Mutation ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Brain Magnetic Resonance Imaging ◽

Comparative Genomic ◽

Feeding Difficulties ◽

Whole Exome

AbstractIntellectual disability is a common condition with multiple etiologies. The number of monogenic causes has increased steadily in recent years due to the implementation of next generation sequencing. Here, we describe a 2-year-old boy with global developmental delay and intellectual disability. The child had feeding difficulties since birth. He had delayed motor skills and muscular hypotonia. Brain magnetic resonance imaging revealed diffuse white matter loss and thinning of the corpus callosum. Banded karyotype and comparative genomic hybridization (CGH) array were normal. Whole exome sequencing revealed a novel de novo frameshift mutation c.3390delA (p.Lys1130Asnfs*4) in KAT6A gene (NM_006766.4). The heterozygous mutation was confirmed by Sanger sequencing in the patient and its absence in his parents. KAT6A that encodes a histone acetyltransferase has been recently found to be associated with a neurodevelopmental disorder autosomal dominant mental retardation 32 (OMIM: no. 616268). Features of this disorder are nonspecific, which makes it difficult to characterize the condition based on the clinical symptoms alone. Therefore, our findings confirm the utility of whole exome sequencing to quickly and reliably identify the etiology of such conditions.

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Correction: A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

European Journal of Human Genetics ◽

10.1038/s41431-021-00937-3 ◽

2021 ◽

Author(s):

Elke de Boer ◽

Charlotte W. Ockeloen ◽

Leslie Matalonga ◽

Rita Horvath ◽

Enzo Cohen ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Whole Exome ◽

Spastic Tetraparesis

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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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Prenatal diagnosis by whole exome sequencing in a family with a novel TBR1 mutation causing intellectual disability

Taiwanese Journal of Obstetrics and Gynecology ◽

10.1016/j.tjog.2021.09.023 ◽

2021 ◽

Vol 60 (6) ◽

pp. 1094-1097

Author(s):

Chunyan Jin ◽

Hua Qian ◽

Tianhui Xu ◽

Jiao Chen ◽

Xuefang Li ◽

...

Keyword(s):

Intellectual Disability ◽

Prenatal Diagnosis ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Whole Exome

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Multiple Variant Calling Pipelines in Wheat Whole Exome Sequencing

International Journal of Molecular Sciences ◽

10.3390/ijms221910400 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10400

Author(s):

H. Busra Cagirici ◽

Bala Ani Akpinar ◽

Taner Z. Sen ◽

Hikmet Budak

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Variant Calling ◽

High Sensitivity ◽

Whole Exome ◽

The Impact ◽

Multiple Reference ◽

Reference Genomes ◽

Selection Of ◽

Variant Identification

The highly challenging hexaploid wheat (Triticum aestivum) genome is becoming ever more accessible due to the continued development of multiple reference genomes, a factor which aids in the plight to better understand variation in important traits. Although the process of variant calling is relatively straightforward, selection of the best combination of the computational tools for read alignment and variant calling stages of the analysis and efficient filtering of the false variant calls are not always easy tasks. Previous studies have analyzed the impact of methods on the quality metrics in diploid organisms. Given that variant identification in wheat largely relies on accurate mining of exome data, there is a critical need to better understand how different methods affect the analysis of whole exome sequencing (WES) data in polyploid species. This study aims to address this by performing whole exome sequencing of 48 wheat cultivars and assessing the performance of various variant calling pipelines at their suggested settings. The results show that all the pipelines require filtering to eliminate false-positive calls. The high consensus among the reference SNPs called by the best-performing pipelines suggests that filtering provides accurate and reproducible results. This study also provides detailed comparisons for high sensitivity and precision at individual and population levels for the raw and filtered SNP calls.

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