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The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes, LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations of LGI1 and LGI4 are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with either LGI2 or LGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants in LGI3 and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generated Lgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. Deep phenotypic characterization showed LGI3 LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants in LGI3 cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3.
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Mioquimia , Proteínas do Tecido Nervoso , Animais , Autoanticorpos , Axônios , Genômica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mamíferos/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Fenótipo , Genética ReversaRESUMO
BACKGROUND: Human coenzyme Q4 (COQ4) is essential for coenzyme Q10 (CoQ10) biosynthesis. Pathogenic variants in COQ4 cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency. METHODS: Clinical course and neuroradiological findings in a large cohort of paediatric patients with COQ4 deficiency were analysed. Functional studies in patient-derived cell lines were performed. RESULTS: We characterised 44 individuals from 36 families with COQ4 deficiency (16 newly described). A total of 23 different variants were identified, including four novel variants in COQ4. Correlation analyses of clinical and neuroimaging findings revealed three disease patterns: type 1: early-onset phenotype with neonatal brain anomalies and epileptic encephalopathy; type 2: intermediate phenotype with distinct stroke-like lesions; and type 3: moderate phenotype with non-specific brain pathology and a stable disease course. The functional relevance of COQ4 variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ10 and elevated levels of the metabolic intermediate 6-demethoxyubiquinone. CONCLUSION: Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of COQ4 variants. Due to the insufficient clinical response to oral CoQ10 supplementation, alternative treatment strategies are warranted.
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Proteínas Mitocondriais , Ubiquinona , Linhagem Celular , Criança , Humanos , Recém-Nascido , Proteínas Mitocondriais/genética , Neuroimagem , Fenótipo , Ubiquinona/genética , Ubiquinona/metabolismoRESUMO
PURPOSE: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency. METHODS: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24. RESULTS: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease. CONCLUSION: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.
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Haploinsuficiência , Deficiência Intelectual , Animais , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/genética , Camundongos , Hipotonia Muscular , Mutação de Sentido Incorreto , FenótipoRESUMO
Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA, MIM#618278) is a rare clinical condition caused by bi-allelic variants in NHL repeat containing protein 2 (NHLRC2, MIM*618277). Pulmonary disease may be the presenting sign and the few patients reported so far, all deceased in early infancy. Exome sequencing was performed on patients with childhood interstitial lung disease (chILD) and additional neurological features. The chILD-EU register database and an in-house database were searched for patients with NHLRC2 variants and clinical features overlapping FINCA syndrome. Six patients from three families were identified with bi-allelic variants in NHLRC2. Two of these children died before the age of two while four others survived until childhood. Interstitial lung disease was pronounced in almost all patients during infancy and stabilized over the course of the disease with neurodevelopmental delay (NDD) evolving as the key clinical finding. We expand the phenotype of FINCA syndrome to a multisystem disorder with variable severity. FINCA syndrome should also be considered in patients beyond infancy with NDD and a history of distinct interstitial lung disease. Managing patients in registers for rare diseases helps identifying new diagnostic entities and advancing care for these patients.
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Angiomatose/diagnóstico , Angiomatose/genética , Fibrose/diagnóstico , Fibrose/genética , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Fenótipo , Alelos , Biópsia , Fácies , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Radiografia , Síndrome , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Keratoconus (KC) is usually bilateral, noninflammatory progressive corneal ectasia in which the cornea becomes progressively thin and conical, resulting in myopia, irregular astigmatism, and corneal scarring. METHODS: Eight families characterized by consanguineous marriages and/or multiple keratoconic individuals were examined genetically. Whole exome sequencing was done as trio or quadro per family. The output of the filtration procedure, based on minor allele frequency (MAF) less than 0.01 for homozygous variants and MAF equals 0 for heterozygous variants, is 22 missense variants. RESULTS: Based on the gene/protein function five candidate variants were highlighted in four families. Two variants were highlighted in one family within the genes MYOF and STX2, and one variant is highlighted in each of the other three families within the genes: COL6A5, ZNF676 and ZNF765. CONCLUSION: This study is one of the very rare that highlights genetic variants in association with KC.
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Sequenciamento do Exoma/métodos , Predisposição Genética para Doença/genética , Ceratocone/genética , Mutação , Proteínas de Ligação ao Cálcio/genética , Colágeno Tipo VI/genética , Consanguinidade , Proteínas de Ligação a DNA/genética , Saúde da Família , Feminino , Humanos , Jordânia , Ceratocone/diagnóstico , Masculino , Proteínas de Membrana/genética , Proteínas Musculares/genética , Linhagem , Sintaxina 1/genéticaRESUMO
TATA-box binding protein associated factor, RNA polymerase I subunit C (TAF1C) is a component of selectivity factor 1 belonging to RNA polymerase I (Pol I) transcription machinery. We report two unrelated patients with homozygous TAF1C missense variants and an early onset neurological phenotype with severe global developmental delay. Clinical features included lack of speech and ambulation and epilepsy. MRI of the brain demonstrated widespread cerebral atrophy and frontal periventricular white matter hyperintensity. The phenotype resembled that of a previously described variant of UBTF, which encodes another transcription factor of Pol I. TAF1C variants were located in two conserved amino acid positions and were predicted to be deleterious. In patient-derived fibroblasts, TAF1C mRNA and protein expression levels were substantially reduced compared with healthy controls. We propose that the variants impairing TAF1C expression are likely pathogenic and relate to a novel neurological disease. This study expands the disease spectrum related to Pol I transcription machinery, associating the TAF1C missense variants with a severe neurological phenotype for the first time.
Assuntos
Epilepsia/genética , RNA Polimerase I/genética , Espasmos Infantis/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Pré-Escolar , Epilepsia/diagnóstico por imagem , Epilepsia/patologia , Feminino , Fibroblastos/metabolismo , Homozigoto , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto/genética , Fenótipo , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/patologiaRESUMO
We recruited 103 families from Jordan with neurodevelopmental disorders (NDD) and patterns of inheritance mostly suggestive of autosomal recessive inheritance. In each family, we investigated at least one affected individual using exome sequencing and an in-house diagnostic variant interpretation pipeline including a search for copy number variation. This approach led us to identify the likely molecular defect in established disease genes in 37 families. We could identify 25 pathogenic nonsense and 11 missense variants as well as 3 pathogenic copy number variants and 1 repeat expansion. Notably, 11 of the disease-causal variants occurred de novo. In addition, we prioritized a homozygous frameshift variant in PUS3 in two sisters with intellectual disability. To our knowledge, PUS3 has been postulated only recently as a candidate disease gene for intellectual disability in a single family with three affected siblings. Our findings provide additional evidence to establish loss of PUS3 function as a cause of intellectual disability.
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Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/genética , Variações do Número de Cópias de DNA/genética , Exoma/genética , Feminino , Mutação da Fase de Leitura/genética , Homozigoto , Humanos , Deficiência Intelectual/patologia , Jordânia/epidemiologia , Masculino , Transtornos do Neurodesenvolvimento/patologia , Linhagem , Irmãos , Sequenciamento do ExomaRESUMO
Epileptic encephalopathies are a catastrophic group of epilepsies characterized by refractory seizures and cognitive arrest, often resulting from abnormal brain development. Here, we have identified an epileptic encephalopathy additionally featuring cerebral calcifications and coarse facial features caused by recessive loss-of-function mutations in DENND5A. DENND5A contains a DENN domain, an evolutionarily ancient enzymatic module conferring guanine nucleotide exchange factor (GEF) activity to multiple proteins serving as GEFs for Rabs, which are key regulators of membrane trafficking. DENND5A is detected predominantly in neuronal tissues, and its highest levels occur during development. Knockdown of DENND5A leads to striking alterations in neuronal development. Mechanistically, these changes appear to result from upregulation of neurotrophin receptors, leading to enhanced downstream signaling. Thus, we have identified a link between a DENN domain protein and neuronal development, dysfunction of which is responsible for a form of epileptic encephalopathy.
Assuntos
Encéfalo/patologia , Epilepsia/genética , Mutação , Proteínas rab de Ligação ao GTP/genética , Adolescente , Animais , Criança , Consanguinidade , Feminino , Fatores de Troca do Nucleotídeo Guanina , Humanos , Masculino , Neurônios/metabolismo , Células PC12 , Linhagem , RatosRESUMO
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.
Assuntos
Aciltransferases/genética , Transtorno Autístico/genética , Epilepsia/genética , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Mutação , Aciltransferases/metabolismo , Ácido Araquidônico/metabolismo , Transtorno Autístico/complicações , Transtorno Autístico/enzimologia , Transtorno Autístico/metabolismo , Criança , Pré-Escolar , Consanguinidade , Epilepsia/complicações , Epilepsia/enzimologia , Epilepsia/metabolismo , Feminino , Homozigoto , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/enzimologia , Deficiência Intelectual/metabolismo , Lisofosfolipídeos/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Linhagem , Fosfatidilinositóis/metabolismoRESUMO
Dopa-responsive dystonia due to sepiapterin reductase deficiency (OMIM#612716) is caused by recessive mutations in the gene encoding sepiapterin reductase (SPR), which plays an important role in the biosynthesis of tetrahydrobiopterin (BH4). One Jordanian patient to first cousin parents is reported in this study. The parents of the proband have recognized the symptoms of their daughter at six months old with motor developmental delay. The symptoms were progressed after-then to include speech delay, seizure, ataxia, oculomotor apraxia, dysarthia and choreoathetosis. Despite of these symptoms, the clinicians in Jordan were unable to diagnose the case. In August 2018, the proband (8 years old) was presented to the department of biotechnology and genetic engineering at Philadelphia University in Jordan for the purposes of performing whole exome sequencing (WES). Analysis of WES data has revealed novel homozygous frameshift variant in the gene SPR (NM_003124.4:c.40delG,p.Ala15Profs*100). The variant is heterozygous in the parents and in the healthy male siblings. Therefore, the studied case was diagnosed with sepiapterin reductase deficiency. Because this disease is likely to be treated recommendations were given to the family immediately to start treatments trials. The case in this study illustrates the difficulties of diagnosing sepiapterin reductase deficiency based on clinical symptoms only and thus renders the possibilities of early management. Also, this study reinforces the importance of running WES to undiagnosed neurodevelopmental cases.
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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.
Assuntos
Consanguinidade , Predisposição Genética para Doença , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Deficiência Intelectual/genética , Adolescente , Criança , Cromossomos Humanos/genética , Variações do Número de Cópias de DNA , Família , Feminino , Genótipo , Homozigoto , Humanos , Lactente , Jordânia , Masculino , Linhagem , Adulto JovemRESUMO
Developmental and epileptic encephalopathies (DEEs) are a heterogenous group of epilepsies in which altered brain development leads to developmental delay and seizures, with the epileptic activity further negatively impacting neurodevelopment. Identifying the underlying cause of DEEs is essential for progress toward precision therapies. Here we describe a group of individuals with biallelic variants in DENND5A and determine that variant type is correlated with disease severity. We demonstrate that DENND5A interacts with MUPP1 and PALS1, components of the Crumbs apical polarity complex, which is required for both neural progenitor cell identity and the ability of these stem cells to divide symmetrically. Induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division during neural induction and have an inherent propensity to differentiate into neurons, and transgenic DENND5A mice, with phenotypes like the human syndrome, have an increased number of neurons in the adult subventricular zone. Disruption of symmetric cell division following loss of DENND5A results from misalignment of the mitotic spindle in apical neural progenitors. A subset of DENND5A is localized to centrosomes, which define the spindle poles during mitosis. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state and ultimately shortening the period of neurogenesis. This study provides a mechanism behind DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.
RESUMO
Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.
Assuntos
Divisão Celular , Células-Tronco Pluripotentes Induzidas , Células-Tronco Neurais , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Humanos , Animais , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Camundongos , Neurogênese/genética , Masculino , Feminino , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Modelos Animais de Doenças , Polaridade CelularRESUMO
Despite major advances in genome technology and analysis, >50% of patients with a neurodevelopmental disorder (NDD) remain undiagnosed after extensive evaluation. A point in case is our clinically heterogeneous cohort of NDD patients that remained undiagnosed after FRAXA testing, chromosomal microarray analysis and trio exome sequencing (ES). In this study, we explored the frequency of non-random X chromosome inactivation (XCI) in the mothers of male patients and affected females, the rationale being that skewed XCI might be masking previously discarded genetic variants found on the X chromosome. A multiplex fluorescent PCR-based assay was used to analyse the pattern of XCI after digestion with HhaI methylation-sensitive restriction enzyme. In families with skewed XCI, we re-evaluated trio-based ES and identified pathogenic variants and a deletion on the X chromosome. Linkage analysis and RT-PCR were used to further study the inactive X chromosome allele, and Xdrop long-DNA technology was used to define chromosome deletion boundaries. We found skewed XCI (>90%) in 16/186 (8.6%) mothers of NDD males and in 12/90 (13.3%) NDD females, far beyond the expected rate of XCI in the normal population (3.6%, OR = 4.10; OR = 2.51). By re-analyzing ES and clinical data, we solved 7/28 cases (25%) with skewed XCI, identifying variants in KDM5C, PDZD4, PHF6, TAF1, OTUD5 and ZMYM3, and a deletion in ATRX. We conclude that XCI profiling is a simple assay that targets a subgroup of patients that can benefit from re-evaluation of X-linked variants, thus improving the diagnostic yield in NDD patients and identifying new X-linked disorders.
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Genes Ligados ao Cromossomo X , Inativação do Cromossomo X , Feminino , Humanos , Masculino , Mães , Alelos , Cromossomos , Cromossomos Humanos X/genética , Proteínas de Neoplasias/genéticaRESUMO
BACKGROUND: Gasdermin A (GSDMA) and Gasdermin B (GSDMB) have been associated with childhood and to a lesser extent with adult asthma in many populations. In this study, we investigate whether there is an association between GSDMA (rs7212938, T/G) and GSDMB (rs7216389, T/C) at locus 17q21.2 and risk of Allergic Rhinitis among Jordanians. Also, we aimed to determine if there is an association between such polymorphisms and the IgE level. METHODS: The study included 112 rhinitis patients and 111 Healthy controls. Gasdermin A (GSDMA) (rs7212938, T/G) and Gasdermin B (rs7216389, T/C) polymorphisms were genotyped using the PCRRFLP method. RESULTS: On the genotype level, three analysis models were applied namely co-dominant, dominant and recessive genotypes. GSDMB CC genotype was found to have a significant protective effect against allergic Rhinitis (< 0.05). cc genotype was also significantly associated with higher IgE level among the studied population. CONCLUSION: The GSDMB CC of homozygous minor genotype showed a protective effect against Allergic rhinitis. It also was found to be significantly associated with lower IgE level among the studied population. No association was found between GSDMA with the risk of allergic Rhinitis.
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Proteínas de Neoplasias/genética , Rinite Alérgica/genética , Adolescente , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Imunoglobulina E/sangue , Jordânia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Rinite Alérgica/sangue , Rinite Alérgica/diagnóstico , Rinite Alérgica/imunologia , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
Leukodystrophies (LDs) are heterogeneous genetic disorders characterized by abnormal white matter in the central nervous system. Some of the LDs are progressive and often fatal. In general, LD is primarily diagnosed based on the neuroimaging; however, definitive diagnosis of the LD type is done using genetic testing such as next-generation sequencing. The aim of this study is to identify the genetic causes of LD in two independent Jordanian cases that exhibit MRI findings confirming LD with no definitive diagnosis using whole exome sequencing (WES). The most likely causative variants were identified. In one case, the homozygous pathogenic variant NM_000049.2:c.914C>A;p.Ala305Glu, which is previously reported in ClinVar, in the gene ASPA was identified causing Canavan disease. In the second case, the homozygous novel variant NM_000487.5:c.256C>G;p.Arg86Gly in the gene ARSA was identified causing metachromatic leukodystrophy. The two variants segregate in their families. The phenotypes of the two studied cases overlap with assigned diseases. The present study raises the importance of using WES to identify the precise neurodevelopmental diseases in Jordan.
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Amidoidrolases/genética , Cerebrosídeo Sulfatase/genética , Sequenciamento do Exoma , Leucodistrofia Metacromática/genética , Adulto , Variações do Número de Cópias de DNA/genética , Exoma/genética , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Lactente , Jordânia , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/diagnóstico por imagem , Leucodistrofia Metacromática/patologia , Masculino , Mutação , Linhagem , Fenótipo , Substância Branca/patologiaRESUMO
BACKGROUND: Keratoconus (KC) is usually bilateral, noninflammatory progressive corneal ectasia in which the cornea becomes progressively thin and conical. Despite the strong evidence of genetic contribution in KC, the etiology of KC is not understood in most cases. METHODS: In this study, we used whole-exome sequencing to identify the genetic cause of KC in two sibs in a consanguineous family. The Homozygous frameshift variant NM_001253826.1:c.60delC;p.Leu21Cysfs*6 was identified in the gene Nacetylgalactosaminyltransferase 14 (GALNT14). The variant does not exist in all public databases neither in our internal exome database. Moreover, no database harbours homozygous loss of function variants in the candidate gene. RESULT: GALNT14 catalyses the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D- galactosamine residue to a serine or threonine residue on target proteins especially Mucins. CONCLUSION: As alterations of mucin's glycosylation are linked to a number of eye diseases, we demonstrate in this study an association between the truncated protein GALNT14 and KC.
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Mutação da Fase de Leitura , Genes Recessivos , Homozigoto , Ceratocone/diagnóstico , Ceratocone/genética , N-Acetilgalactosaminiltransferases/genética , Análise Mutacional de DNA , Feminino , Genoma , Genômica/métodos , Humanos , Linhagem , Sequenciamento do ExomaRESUMO
BACKGROUND: Late infantile ceroid lipofuscinosis is a rare neurodegenerative disorder that appears between the ages of 2 and 4 years and is difficult to diagnose. In this report we present two sisters with this condition, and the clinical course consisted of delayed developmental skills initially and later regression of previously acquired skills. The cases were initially considered as childhood disintegrative disorder (CDD); however, when whole exome sequencing (WES) genetic testing was done, they proved to be variant late infantile ceroid lipofuscinosis. This is the first report from Jordan. CASE SUMMARY: Clinical presentation included developmental delay and initially speech delay, followed by lose of sphincter control. Motor development was normal until 4 years of age, then they developed ataxia (fear of going downstairs) and weakness while walking. Atonic and myoclonic seizures become intractable, and this was followed by inability to stand or sit and loss of expressive language. In addition to complete blood count test, liver function test, kidney function test, serum electrolyte test, and blood sugar test, serum amino acid profile, B12 level test, thyroid function test, and a brain computed tomography scan were also normal. An electroencephalogram showed a generalized spike and wave pattern, and magnetic resonance imaging showed little to no abnormalities. After dealing with the cases as CDD, WES testing proved a final diagnosis of variant late infantile ceroid lipofuscinosis. Current treatment is anti-epileptic drugs and supportive care at home, and they are now in vegetative state. CONCLUSION: This report highlights the importance of WES for the identification of genetic diseases, especially neurodegenerative disorders.
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Importance: Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown. Objectives: To promote the identification of disease genes through confirmation of previously described genes and presentation of novel candidates and provide an overview of the diagnostic yield of exome sequencing in consanguineous families. Design, Setting, and Participants: Autozygosity mapping in families and exome sequencing of index patients were performed in 152 consanguineous families (the parents descended from a same ancestor) with at least 1 offspring with intellectual disability (ID). The study was conducted from July 1, 2008, to June 30, 2015, and data analysis was conducted from July 1, 2015, to August 31, 2016. Results: Of the 152 consanguineous families enrolled, 1 child (in 45 families [29.6%]) or multiple children (107 families [70.4%]) had ID; additional features were present in 140 of the families (92.1%). The mean (SD) age of the children was 10.3 (9.0) years, and 171 of 297 (57.6%) were male. In 109 families (71.7%), potentially protein-disrupting and clinically relevant variants were identified. Of these, a clear clinical genetic diagnosis was made in 56 families (36.8%) owing to 57 (likely) pathogenic variants in 50 genes already established in neurodevelopmental disorders (46 autosomal recessive, 2 X-linked, and 2 de novo) or in 7 previously proposed recessive candidates. In 5 of these families, potentially treatable disorders were diagnosed (mutations in PAH, CBS, MTHFR, CYP27A1, and HIBCH), and in 1 family, 2 disease-causing homozygous variants in different genes were identified. In another 48 families (31.6%), 52 convincing recessive variants in candidate genes that were not previously reported in regard to neurodevelopmental disorders were identified. Of these, 14 were homozygous and truncating in GRM7, STX1A, CCAR2, EEF1D, GALNT2, SLC44A1, LRRIQ3, AMZ2, CLMN, SEC23IP, INIP, NARG2, FAM234B, and TRAP1. The diagnostic yield was higher in individuals with severe ID (35 of 77 [45.5%]), in multiplex families (42 of 107 [39.3%]), in patients with additional features (30 of 70 [42.9%]), and in those with remotely related parents (15 of 34 [44.1%]). Conclusions and Relevance: Because of the high diagnostic yield of 36.8% and the possibility of identifying treatable diseases or the coexistence of several disease-causing variants, using exome sequencing as a first-line diagnostic approach in consanguineous families with neurodevelopmental disorders is recommended. Furthermore, the literature is enriched with 52 convincing candidate genes that are awaiting confirmation in independent families.
Assuntos
Consanguinidade , Exoma/genética , Genes Recessivos/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Transtornos do Neurodesenvolvimento/genética , Análise de Sequência de DNA , Criança , Aberrações Cromossômicas , Análise Mutacional de DNA , Feminino , Alemanha , Homozigoto , Humanos , MasculinoRESUMO
INTRODUCTION: Gasdermin A (GSDMA) and gasdermin B (GSDMB) have been associated with childhood, and to a lesser extent with adult, asthma in many populations. AIMS: In this study, we investigated the association between GSDMA and GSDMB variants and the incidence of adult and childhood asthma among Jordanians. METHODS: Subjects were divided into two groups: adults and children. Within the adult group there were 129 asthma patients and 111 healthy controls. In the pediatric group there were 98 asthma patients and 112 healthy children. Gasdermin A (GSDMA) (rs7212938, T/G) and Gasdermin B (rs7216389, T/C) polymorphisms were genotyped using the PCR-RFLP method. Three analysis models were applied to the genotype data: co-dominant, dominant and recessive. RESULTS: An association between the GSDMB T/C single nucleotide polymorphism (SNP) genotype and the incidence of childhood asthma was found (< 0.05). GSDMB T/C SNP in children also showed a very high tendency toward significance with p = 0.0532 in the single locus analysis. In adults, no significant differences in the allelic frequencies of any of the SNPs analyzed were found between the case and control populations. At the haplotype level, GC haplotype was found to be associated with the risk of asthma in children while none of the tested haplotypes were found to be associated with asthma risk in adults. CONCLUSIONS: The findings of this study confirm the previously reported association between the GSDMB gene and the risk of childhood asthma.