Autosomal Recessive Variants in Intellectual Disability and Autism Spectrum Disorder

The development of the nervous system is a tightly timed and controlled process where aberrant development may lead to neurodevelopmental disorders. Two of the most common forms of neurodevelopmental disorders are Intellectual Disability (ID) and Autism Spectrum Disorder (ASD). These two disorders are intertwined, but much about the etiological relationship between them remains a mystery. Little attention has been given to the role recessive variants play in ID and ASD, perhaps related to the ability of recessive variants to remain hidden in the population. This thesis aims to help determine the role of recessive variants in ID and ASD and identify novel genes associated with these neurodevelopmental disorders. Technological advancements such as Next Generation Sequencing (NGS) and large population-scale sequencing reference sets have ushered in a new era of high throughput gene identification. In total, 307 families were whole-exome sequenced (192 consanguineous multiplex ID families and 115 consanguineous trio ASD families), representing 537 samples in total. This work identified 26 novel genes for ID such as ABI2, MAPK8, MBOAT7, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7, and USP44 in large multiplex families with an overall diagnostic yield of 51 %. ASD often has other comorbid features and the connection with ID and ASD has been observed in literature with an estimated 40-70% if ASD probands also have comorbid ID. Extending the use of consanguineous families in autosomal recessive variant identification in ASD, the diagnostic yield for this ASD trio cohort was ~26 %, with 28 of the known variants coming from previously known genes. This study identified putative variants with functional mouse models that display behavioural and nervous system abnormalities involving genes such as EPHB1, VPS16, CNGA2 and EFR3B. Of the neurodevelopmental genes from this cohort, ZNF292 is the most associated with ID with or without syndromic features and ASD. The overall body of work highlights the clinical and genetic heterogeneity in neurodevelopmental disorders and demonstrates the important role that recessive variants have in neurodevelopment disorders, including ASD. The identification of novel genes will hopefully provide better diagnosis and clinical management for patients.Ph.D

Biallelic Loss of Function Mutation in Sodium Channel Gene <i>SCN10A</i> in an Autism Spectrum Disorder Trio from Pakistan

The genetic dissection of autism spectrum disorders (ASD) has uncovered the contribution of de novo mutations in many single genes as well as de novo copy number variants. More recent work also suggests a strong contribution from recessively inherited variants, particularly in populations in which consanguineous marriages are common. What is also becoming more apparent is the degree of pleiotropy, whereby mutations in the same gene may have quite different phenotypic and clinical consequences. We performed whole exome sequencing in a group of 115 trios from countries with a high level of consanguineous marriages. In this paper we report genetic and clinical findings on a proband with ASD, who inherited a biallelic truncating pathogenic/likely pathogenic variant in the gene encoding voltage-gated sodium channel X alpha subunit, SCN10A (NM_006514.2:c.937G>T:(p.Gly313*)). The biallelic pathogenic/likely pathogenic variant in this study have different clinical features than heterozygous mutations in the same gene. The study of consanguineous families for autism spectrum disorder is highly valuable

Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features

WOS: 000385333700011PubMed ID: 27616480The risk of epilepsy among individuals with intellectual disability (ID) is approximately ten times that of the general population. From a cohort of >5,000 families affected by neurodevelopmental disorders, we identified six consanguineous families harboring homozygous inactivating variants in MBOAT7, encoding lysophosphatidylinositol acyltransferase (LPIAT1). Subjects presented with ID frequently accompanied by epilepsy and autistic features. LPIAT1 is a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid (AA) to lysophosphatidylinositol to produce AA-containing phosphatidylinositol. This study suggests a role for AA-containing phosphatidylinositols in the development of ID accompanied by epilepsy and autistic features.Howard Hughes Medical Institute; National Institute of Neurological Disorders and Stroke [R01NS098004, R01NS048453]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [P01HD070494]; Qatar National Research Fund [NPRP6-1463]; Simons Foundation Autism Research Initiative [175303, 275275]; Deutsche Forschungsgemeinschaft (DFG) [AB393/2-2, AB393/4-1]; Canadian Institutes of Health Research [MOP-102758]; Pakistani Higher Education CommissionWe are grateful to the affected individuals and their families for their participation in the study. This study was supported by the Howard Hughes Medical Institute, National Institute of Neurological Disorders and Stroke (R01NS098004 and R01NS048453), Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD070494), Qatar National Research Fund (NPRP6-1463), and Simons Foundation Autism Research Initiative (175303 and 275275). We thank the Broad Institute (U54HG003067 to E. Lander and HG00 8900 to D. MacArthur) and the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton, M. Gunel, M. Gerstein, and S. Mane) for sequencing support and analysis. This study was partially supported by grants from the Deutsche Forschungsgemeinschaft (DFG) to R.A.J. (AB393/2-2 and AB393/4-1), a grant from the Canadian Institutes of Health Research to J.B.V. (MOP-102758), and an award from the Pakistani Higher Education Commission to I.A

Heterozygous Truncating Mutation of Nucleolin in an ASD Individual Disrupts Its Nucleolar Localization

Nucleolin (NCL/C23; OMIM: 164035) is a major nucleolar protein that plays a critical role in multiple processes, including ribosome assembly and maturation, chromatin decondensation, and pre-rRNA transcription. Due to its diverse functions, nucleolin has frequently been implicated in pathological processes, including cancer and viral infection. We recently identified a frameshifting indel mutation of , p.Gly664Glufs*70, through whole-exome sequencing of autism spectrum disorder trios. Through the transfection of constructs encoding either a wild-type human nucleolin or a mutant nucleolin with the same C-terminal sequence predicted for the autism proband, and by using co-localization with the nucleophosmin (NPM; B23) protein, we have shown that the nucleolin mutation leads to mislocalization of the NCL protein from the nucleolus to the nucleoplasm. Moreover, a construct with a nonsense mutation at the same residue, p.Gly664*, shows a very similar effect on the location of the NCL protein, thus confirming the presence of a predicted nucleolar location signal in this region of the NCL protein. Real-time fluorescence recovery experiments show significant changes in the kinetics and mobility of mutant NCL protein in the nucleoplasm of HEK293Tcells. Several other studies also report mutations in ASD or neurodevelopmental disorders. The altered mislocalization and dynamics of mutant NCL (p.G664Glufs*70/p.G664*) may have relevance to the etiopathlogy of -related ASD and other neurodevelopmental phenotypes

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

Heterozygous De Novo Truncating Mutation of Nucleolin in an ASD Individual Disrupts Its Nucleolar Localization

Nucleolin (NCL/C23; OMIM: 164035) is a major nucleolar protein that plays a critical role in multiple processes, including ribosome assembly and maturation, chromatin decondensation, and pre-rRNA transcription. Due to its diverse functions, nucleolin has frequently been implicated in pathological processes, including cancer and viral infection. We recently identified a de novo frameshifting indel mutation of NCL, p.Gly664Glufs*70, through whole-exome sequencing of autism spectrum disorder trios. Through the transfection of constructs encoding either a wild-type human nucleolin or a mutant nucleolin with the same C-terminal sequence predicted for the autism proband, and by using co-localization with the nucleophosmin (NPM; B23) protein, we have shown that the nucleolin mutation leads to mislocalization of the NCL protein from the nucleolus to the nucleoplasm. Moreover, a construct with a nonsense mutation at the same residue, p.Gly664*, shows a very similar effect on the location of the NCL protein, thus confirming the presence of a predicted nucleolar location signal in this region of the NCL protein. Real-time fluorescence recovery experiments show significant changes in the kinetics and mobility of mutant NCL protein in the nucleoplasm of HEK293Tcells. Several other studies also report de novoNCL mutations in ASD or neurodevelopmental disorders. The altered mislocalization and dynamics of mutant NCL (p.G664Glufs*70/p.G664*) may have relevance to the etiopathlogy of NCL-related ASD and other neurodevelopmental phenotypes

Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features

The risk of epilepsy among individuals with intellectual disability (ID) is approximately ten times that of the general population. From a cohort of >5,000 families affected by neurodevelopmental disorders, we identified six consanguineous families harboring homozygous inactivating variants in MBOAT7, encoding lysophosphatidylinositol acyltransferase (LPIAT1). Subjects presented with ID frequently accompanied by epilepsy and autistic features. LPIAT1 is a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid (AA) to lysophosphatidylinositol to produce AA-containing phosphatidylinositol. This study suggests a role for AA-containing phosphatidylinositols in the development of ID accompanied by epilepsy and autistic features

Mutations in MBOAT7 , Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features

The risk of epilepsy among individuals with intellectual disability (ID) is approximately ten times that of the general population. From a cohort of >5,000 families affected by neurodevelopmental disorders, we identified six consanguineous families harboring homozygous inactivating variants in MBOAT7, encoding lysophosphatidylinositol acyltransferase (LPIAT1). Subjects presented with ID frequently accompanied by epilepsy and autistic features. LPIAT1 is a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid (AA) to lysophosphatidylinositol to produce AA-containing phosphatidylinositol. This study suggests a role for AA-containing phosphatidylinositols in the development of ID accompanied by epilepsy and autistic features