Iranome: A catalog of genomic variations in the Iranian population

Fattahi, Zohreh; Beheshtian, Maryam; Mohseni, Marzieh; Poustchi, Hossein; Sellars, Erin; Nezhadi, Sayyed Hossein; Amini, Amir; Arzhangi, Sanaz; Jalalvand, Khadijeh; Jamali, Peyman; Mohammadi, Zahra; Davarnia, Behzad; Nikuei, Pooneh; Oladnabi, Morteza; Mohammadzadeh, Akbar; Zohrehvand, Elham; Nejatizadeh, Azim; Shekari, Mohammad; Bagherzadeh, Maryam; Gooshki, Ehsan Shamsi; Börno, Stefan T.; Timmermann, Bernd; Haghdoost, Ali-Akbar; Najafipour, Reza; Khorshid, Hamid Reza Khorram; Kahrizi, Kimia; Malekzadeh, Reza; Akbari, Mohammad Reza; Najmabadi, Hossein

doi:10.1002/humu.23880

Cited by 125 publications

(91 citation statements)

References 43 publications

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“…All seven identified GRM7 variants were absent in the homozygous state from public variant databases including the Genome Aggregation Database (gnomAD), the Exome Aggregation Consortium (ExAC), the Atherosclerosis Risk in Communities Study Database (ARIC), and the National Heart, Lung, and Blood Institute (NHLBI) Grand Opportunity Exome Sequencing Project (ESP) as well as from our in‐house control database. The variants were also absent in heterozygous and homozygous state from the Iranome database (http://www.iranome.com) that contains exomes of 100 healthy individuals from related ethnic groups 25 . Three variants (RefSeq: NM_000844.4; c.461T>C, c.1972C>T, and c.2024C>A) were entered by our group into a public archive of human variation and phenotypes (ClinVar) following the publication of the initial cohort (ClinVar accession numbers VCV000242895, VCV000242900, and VCV000242901, respectively) 21 .…”

Section: Methodsmentioning

confidence: 99%

Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Marafi

Mitani

Işıkay³

et al. 2020

Ann Clin Transl Neurol

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Objective: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-proteincoupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families. Methods: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory. Results: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T: p.Arg659Ter). Developmental delay, neonatal-or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late 610 childhood. Conclusion: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.

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Section: Methodsmentioning

confidence: 99%

Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Marafi

Mitani

Işıkay³

et al. 2020

Ann Clin Transl Neurol

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“…of UGP2 isoform 2 (NM_001001521), referred to as long and short isoform, respectively. The variant has not been reported in the Epi25 web browser 36 , ClinVar 37 , LOVD 38 , Exome Variant Server 39 , DECIPHER 40 , GENESIS 41 , GME variome 42 or Iranome databases 43 , is absent from our in-house data bases and is found only 15 times in a heterozygous, but not homozygous, state in the 280,902 alleles present in gnomAD (MAF: 0.00005340) 44 . In the GeneDx unaffected adult cohort, the variant was found heterozygous 10 times out of 173,502 alleles (MAF: 0.00005764), in the ∼10,000 exomes of the Queen Square Genomic Center database two heterozygous individuals were identified, and out of 45,921 individuals in the Centogene cohort, 10 individuals are heterozygous for this variant.…”

Section: Resultsmentioning

confidence: 79%

“…F) Violin plots showing distribution of gene expression (in TPM) amongst male and female samples from the GTEx portal 43 for various brain regions. Outliers are indicated by dots…”

Section: Resultsmentioning

confidence: 99%

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform specific start-loss mutations of essential genes can cause genetic diseases

Perenthaler

Nikoncuk

Yousefi

et al. 2019

Preprint

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2 52 Running title: Loss of UGP2 causes a severe epileptic encephalopathy 53 54 55 Abstract: 60 Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic 61 disorders, resulting in early onset, therapy resistant seizures and developmental delay. Here we 62 report on 12 individuals from 10 families presenting with a severe form of intractable epilepsy, 63 severe developmental delay, progressive microcephaly and visual disturbance. Whole exome 64 sequencing identified a recurrent, homozygous variant (chr2:64083454A>G) in the essential UDP-65 glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable 66Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start 67 codon of the shorter isoform. We show that the absence of the shorter isoform leads to a reduction 68 of functional UGP2 enzyme in brain cell types, leading to altered glycogen metabolism, upregulated 69unfolded protein response and premature neuronal differentiation, as modelled during pluripotent 70 stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to 71 differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in 72 vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our 73 study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive 74 DEE. Importantly, it also shows that isoform specific start-loss mutations causing expression loss of a 75 tissue relevant isoform of an essential protein can cause a genetic disease, even when an organism-76 wide protein absence is incompatible with life. We provide additional examples where a similar 77 disease mechanism applies. 78 79 80 81 82 83 84 85 86 87 3 Introduction: 88 Developmental and/or epileptic encephalopathies (DEEs) are a heterogeneous group of genetic 89 disorders, characterized by severe epileptic seizures in combination with developmental delay or 90 regression 1 . Genes involved in multiple pathophysiological pathways have been implicated in DEEs, 91 including synaptic impairment, ion channel alterations, transporter defects and metabolic processes 92 such as disorders of glycosylation 2 . Mostly, dominant acting, de novo mutations have been identified 93 in children suffering from DEEs 3 , and only a limited number of genes with a recessive mode of 94 inheritance are known so far, with a higher occurrence rate in consanguineous populations 4 . A recent 95 cohort study on DEEs employing whole exome sequencing (WES) and copy-number analysis, 96however, found that up to 38% of diagnosed cases might be caused by recessive genes, indicating 97 that the importance of this mode of inheritance in DEEs has been underestimated 5 . 98

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“…Missense variants were excluded when three out of five in silico pathogenicity prediction tools yielded a benign score. Manual MAF analysis used gnomAD (23), GME (24), and Iranome (25).…”

Section: Genotyping Homozygosity Mapping Copy Number Variation and mentioning

confidence: 99%

Biallelic mutation ofCLRN2causes non-syndromic hearing loss in humans

Vona

Mazaheri

Lin

et al. 2020

Preprint

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Deafness, the most frequent sensory deficit in humans, is extremely heterogenous with hundreds of genes probably involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 15.2 Mb locus on chromosome 4p15.32p15.1 containing a missense pathogenic variant in CLRN2 (c.494C>A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C>A mutation leads to two events: 1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and 2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.

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Iranome: A catalog of genomic variations in the Iranian population

Cited by 125 publications

References 43 publications

Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform specific start-loss mutations of essential genes can cause genetic diseases

Biallelic mutation ofCLRN2causes non-syndromic hearing loss in humans

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