Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders

Reuter, Miriam S.; Tawamie, Hasan; Buchert, Rebecca; Gebril, Ola H.; Froukh, Tawfiq; Thiel, Christian T.; Uebe, Steffen; Ekici, Arif B.; Krumbiegel, Mandy; Zweier, Christiane; Hoyer, Juliane; Eberlein, Karolin; Bauer, Judith; Scheller, Ute; Strom, Tim M.; Hoffjan, Sabine; Abdelraouf, Ehab R.; Meguid, Nagwa A.; Abboud, Ahmad; Khateeb, Mohammed Ayman Al; Fakher, Mahmoud; Hamdan, Saber; Ismael, Amina; Muhammad, Safia; Abdallah, Ebtessam; Sticht, Heinrich; Wieczorek, Dagmar; Jamra, Rami Abou

doi:10.1001/jamapsychiatry.2016.3798

Cited by 182 publications

(172 citation statements)

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“…Seven families have homozygous variants in potentially novel candidate genes for ARID ( CACNG7, CARNMT1 / C9orf41, EI24, GARNL3, FXR1, TRAPPC10, TET3 ; Tables 1, 2). One additional family MR60 with severe ARID has a homozygous stop variant in GRAMD1B and a rare, damaging mis-sense variant in TBRG1 , both of which lie within the mapped region in chromosome 11q23.2-q24.2 and were previously suggested to be candidate genes for ARID (Reuter et al 2017; Hu et al 2018) having been identified in a single ARID family (Table 2). Both replicated ID genes are likely to be sufficient to cause disease etiology but no conclusion can be made on the impact on the phenotype of being a homozygous carrier for variants in both genes.…”

Section: Resultsmentioning

confidence: 99%

“…In a previous publication a missense variant within GRAMD1B was identified in a consanguineous Syrian family with moderate nonsyndromic ID (Reuter et al 2017). On the other hand, a consanguineous Persian family was found to have a frameshift TBRG1 variant co-segregating with severe ARID and developmental delay (Hu et al 2018).…”

Section: Discussionmentioning

confidence: 98%

“…In several published cohorts consisting of predominantly consanguineous ARID families from the Middle East and Pakistan (number of families ranging from 18 to 337), detection rates of putatively causal variants from NGS studies range from 37 to 90% and an aggregate of 327 novel or candidate ARID genes were identified (Najmabadi et al 2011; Yavarna et al 2015; Charng et al 2016; Megahed et al 2016; Riazuddin et al 2017; Anazi et al 2017; Reuter et al 2017; Harripaul et al 2017; Monies et al 2017; Hu et al 2018). …”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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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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“…In an Iranian population, a combination of homozygosity mapping and exome sequencing in 136 consanguineous families with ID revealed: (1) disease-causing mutations in 57% of the studied cases and (2) fifty novel candidate genes (Najmabadi et al 2011). Likewise, in a population from Jordan, seven consanguineous families with nonspecific ID were investigated using next generation sequencing (NGS) and homozygosity mapping (Reuter et al 2017). Mutations responsible for ID were identified in three of the seven families, and several other candidates were also revealed.…”

Section: Introductionmentioning

confidence: 99%

Next Generation Sequencing and Genome-Wide Genotyping Identify the Genetic Causes of Intellectual Disability in Ten Consanguineous Families from Jordan

Froukh

2017

Tohoku J. Exp. Med.

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Intellectual disability (ID), occurs in approximately 1 to 3% of the population and tends to be higher in low-income countries and in inbred communities. Despite the high rates of consanguineous marriages and the likely enrichment for recessive forms of ID, the genetic bases of ID in Jordan are largely unstudied. In this study, whole exome sequencing (WES) and homozygosity mapping were used to identify the genetic causes of ID in ten families from Jordan. The studied families are characterized by consanguineous marriage and having one or more progeny with ID. Likely disease-causing missense mutations were identified in eight families; four families are due to mutations in genes previously implicated with ID and the other four families are due to mutations in genes that are not previously implicated with ID. The novel genes include: BSN (Protein Basson), PTCHD2 (Protein dispatched homolog 3), DHRS3 (Short-chain dehydrogenase/reductase 3), and LGI3 (Leucine-rich repeat LGI family member 3). In addition, copy number variant (CNV) deletion and/or duplication were identified in 2 families; one family with 3.5 mega base (Mb) deletion on chromosome17 previously implicated with Smith Magenis Syndrome, and the other family with a novel combination of deletion and duplication in chromosomes 5 and 11. In this pilot study, four genes and one CNV deletion/duplication are identified for the first time in association with ID. The finding of this study further demonstrates the power of WES and homozygosity mapping for clinical diagnostics of ID in consanguineous families in small populations.

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“…1 In order to illuminate the highly heterogeneous genetic causes of ID, we examined a large cohort of consanguineous families affected by probably autosomal-recessive ID. 2 To support the exchange of information between scientists, we established the Consortium of Autosomal-Recessive Intellectual Disability (CARID), which aims to facilitate the sharing of clinical and molecular data. These efforts led to the identification of two homozygous variants in TATA-box-binding-protein-associated factor 13 (TAF13 [MIM: 600774]) that co-segregate with ID in two independent families.…”

mentioning

confidence: 99%

Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly

Tawamie

Martianov

Wohlfahrt

et al. 2017

The American Journal of Human Genetics

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In two independent consanguineous families each with two children affected by mild intellectual disability and microcephaly, we identified two homozygous missense variants (c.119T>A [p.Met40Lys] and c.92T>A [p.Leu31His]) in TATA-box-binding-protein-associated factor 13 (TAF13). Molecular modeling suggested a pathogenic effect of both variants through disruption of the interaction between TAF13 and TAF11. These two proteins form a histone-like heterodimer that is essential for their recruitment into the general RNA polymerase II transcription factor IID (TFIID) complex. Co-immunoprecipitation in HeLa cells transfected with plasmids encoding TAF11 and TAF13 revealed that both variants indeed impaired formation of the TAF13-TAF11 heterodimer, thus confirming the protein modeling analysis. To further understand the functional role of TAF13, we performed RNA sequencing of neuroblastoma cell lines upon TAF13 knockdown. The transcriptional profile showed significant deregulation of gene expression patterns with an emphasis on genes related to neuronal and skeletal functions and those containing E-box motives in their promoters. Here, we expand the spectrum of TAF-associated phenotypes and highlight the importance of TAF13 in neuronal functions.

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Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders

Cited by 182 publications

References 36 publications

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

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

Next Generation Sequencing and Genome-Wide Genotyping Identify the Genetic Causes of Intellectual Disability in Ten Consanguineous Families from Jordan

Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly

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