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Himanshu Goel

Bio: Himanshu Goel is an academic researcher from University of Newcastle. The author has contributed to research in topics: Medicine & Gene. The author has an hindex of 13, co-authored 36 publications receiving 503 citations. Previous affiliations of Himanshu Goel include University of Melbourne & John Hunter Hospital.

Papers
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Journal ArticleDOI
TL;DR: It is shown that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood.
Abstract: Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

101 citations

Journal ArticleDOI
TL;DR: Identifying ARMC9 mutations as a cause of Joubert syndrome takes us one step closer to a full genetic understanding of this important disorder and enables future functional work to define the central biological mechanisms underlying JS and other ciliopathies.
Abstract: Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, abnormal eye movements, and variable cognitive impairment. It is defined by a distinctive brain malformation known as the "molar tooth sign" on axial MRI. Subsets of affected individuals have malformations such as coloboma, polydactyly, and encephalocele, as well as progressive retinal dystrophy, fibrocystic kidney disease, and liver fibrosis. More than 35 genes have been associated with JS, but in a subset of families the genetic cause remains unknown. All of the gene products localize in and around the primary cilium, making JS a canonical ciliopathy. Ciliopathies are unified by their overlapping clinical features and underlying mechanisms involving ciliary dysfunction. In this work, we identify biallelic rare, predicted-deleterious ARMC9 variants (stop-gain, missense, splice-site, and single-exon deletion) in 11 individuals with JS from 8 families, accounting for approximately 1% of the disorder. The associated phenotypes range from isolated neurological involvement to JS with retinal dystrophy, additional brain abnormalities (e.g., heterotopia, Dandy-Walker malformation), pituitary insufficiency, and/or synpolydactyly. We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. Typical ciliopathy phenotypes (curved body shape, retinal dystrophy, coloboma, and decreased cilia) in a CRISPR/Cas9-engineered zebrafish mutant model provide additional support for ARMC9 as a ciliopathy-associated gene. Identifying ARMC9 mutations as a cause of JS takes us one step closer to a full genetic understanding of this important disorder and enables future functional work to define the central biological mechanisms underlying JS and other ciliopathies.

70 citations

Journal ArticleDOI
TL;DR: POLE is established as a second gene in which mutations cause IMAGe syndrome, adding to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.
Abstract: During genome replication, polymerase epsilon (Pol e) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol e catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol e and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.

62 citations

Journal ArticleDOI
TL;DR: It is found that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous, and eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain.
Abstract: OBJECTIVE: Determining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS). METHODS: Precise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates. RESULTS: Thirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n = 10; CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142) or copy number (n = 1; 5q14.3q21.1 locus) variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain. CONCLUSION: We identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches.

55 citations

Journal ArticleDOI
TL;DR: The molecular basis of MFDM is reviewed in the 69 individuals described to date, and mutations in 38 new individuals are reported, bringing the total number of reported individuals to 107 individuals from 94 kindreds.
Abstract: Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).

49 citations


Cited by
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Journal ArticleDOI
TL;DR: WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness.

372 citations

Journal ArticleDOI
TL;DR: A novel classification of leukodystrophies is proposed that takes into account the primary involvement of any white matter component, and Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin; astrocytopathies; leuko-axonopathies; microgliopathy; andLeuko-vasculopathies.
Abstract: Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies.

216 citations

01 Jan 2017
TL;DR: A centralized analysis pipeline was applied to a SCZ cohort of 21,094 cases and 20,227 controls and Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.
Abstract: Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10−15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

173 citations

Journal ArticleDOI
Dorota Monies1, M. Abouelhoda1, Mirna Assoum, Nabil Moghrabi1, Rafiullah Rafiullah, Naif A.M. Almontashiri2, Mohammed Al-Owain, Hamad Al-Zaidan, Moeen Al-Sayed, Shazia Subhani1, Edward Cupler, Maha Faden, Amal Alhashem, Alya Qari, Aziza Chedrawi, Hisham Aldhalaan, Wesam Kurdi, Sameena Khan, Zuhair Rahbeeni, Maha Alotaibi, Ewa Goljan1, Hadeel Elbardisy, Mohamed El-Kalioby1, Zeeshan Shah1, Hibah Alruwaili1, Amal Jaafar1, Ranad Albar1, Asma Akilan, Hamsa T. Tayeb1, Asma I. Tahir1, Mohammed Fawzy1, Mohammed Nasr1, Shaza Makki, Abdullah Alfaifi, Hanna Akleh, Suad Al Yamani, Dalal K. Bubshait, Mohammed Mahnashi, Talal A. Basha, Afaf Alsagheir, Musad Abu Khaled, Khalid Alsaleem, Maisoon Almugbel, Manal Badawi, Fahad A. Bashiri3, Saeed Bohlega, Raashida Sulaiman, Ehab Tous, Syed Ahmed, Talal Algoufi, Hamoud Al-Mousa, Emadia Alaki, Susan Alhumaidi4, Hadeel Alghamdi, Malak Alghamdi4, Ahmed Sahly, Shapar Nahrir4, Ali Al-Ahmari5, Hisham Alkuraya, Ali Al-Mehaidib, Mohammed Abanemai, Fahad Alsohaibaini, Bandar Al-Saud, Rand Arnaout, Ghada M H Abdel-Salam, Hasan Al-Dhekri, Suzan A AlKhater6, Khalid S. Alqadi, Essam Al-Sabban, Turki Alshareef, Khalid Awartani, Hanaa Banjar, Nada Alsahan, Ibraheem F. Abosoudah, Abdullah Alashwal, Wajeeh Aldekhail, Sami Al-Hajjar, Sulaiman M. Al-Mayouf, Abdulaziz Alsemari, Walaa Alshuaibi3, Saeed Altala, Abdulhadi Altalhi4, Salah Baz, Muddathir H Hamad3, Tariq Abalkhail, Badi Alenazi, Alya Alkaff, Fahad Almohareb, Fuad Al Mutairi7, Fuad Al Mutairi8, Mona Alsaleh, Abdullah Alsonbul, Somaya Alzelaye, Shakir Bahzad, Abdulaziz Bin Manee, Ola Jarrad, Neama Meriki3, Bassem Albeirouti, Amal Alqasmi4, Mohammed AlBalwi7, Nawal Makhseed, Saeed Hassan3, Isam Salih, Mustafa A. Salih3, Marwan Shaheen, Saadeh Sermin, Shamsad Shahrukh, Shahrukh K. Hashmi, Ayman Shawli8, Ameen Tajuddin, Abdullah Tamim, Ahmed Alnahari, Ibrahim Ghemlas, Maged H. Hussein, Sami Wali, Hatem Murad, Brian F. Meyer1, Fowzan S. Alkuraya1, Fowzan S. Alkuraya5 
TL;DR: The influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome) is described and the cohort's genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing.
Abstract: We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort's genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing.

165 citations

Journal ArticleDOI
TL;DR: The data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.
Abstract: Developmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios. Whole-exome sequences (WES) were generated for 365 individuals (127 affected) and whole-genome sequences (WGS) were generated for 612 individuals (244 affected). Pathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected first-degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses, we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS and 4.7% of families with a negative result eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGaP. Our data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.

155 citations