RESUMEN
BACKGROUND: Neuronal ceroid lipofuscinoses (NCLs) represent a heterogeneous group of inherited metabolic lysosomal disorders characterized by neurodegeneration. This study sought to describe the clinical and molecular characteristics of NCLs in Saudi Arabia and determine the most common types in that population. METHODS: A retrospective review of electronic medical records was conducted for 63 patients with NCL (55 families) from six tertiary and referral centers in Saudi Arabia between 2008 and 2022. Clinical, radiological, and neurophysiological data as well as genetic diagnoses were reviewed. RESULTS: CLN6 was the predominant type, accounting for 45% of cases in 25 families. The most common initial symptoms were speech delay (53%), cognitive decline (50%) and/or gait abnormalities (48%), and seizure (40%). Behavioral symptomatology was observed in 20%, whereas visual impairment was less frequently (9.3%) encountered. Diffuse cerebral and cerebellar atrophy was the predominant finding on brain magnetic resonance imaging. Electroencephalography generally revealed background slowing in all patients with generalized epileptiform discharges in 60%. The most common genotype detected was the p.Ser265del variant found in 36% (20 of 55 families). The most rapidly progressive subtypes were CLN2 and CLN6. Two patients with each died at age five years. The earliest age at which a patient was nonambulatory was two years in a patient with CLN14. CONCLUSIONS: This is the largest molecularly confirmed NCL cohort study from Saudi Arabia. Characterizing the natural history of specific NLC types can increase understanding of the underlying pathophysiology and distinctive genotype-phenotype characteristics, facilitating early diagnosis and treatment initiation as well as genetic counseling for families.
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Lipofuscinosis Ceroideas Neuronales , Tripeptidil Peptidasa 1 , Humanos , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/fisiopatología , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Arabia Saudita , Masculino , Femenino , Niño , Preescolar , Estudios Retrospectivos , Adolescente , Proteínas de la Membrana/genética , Lactante , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Adulto Joven , Imagen por Resonancia MagnéticaRESUMEN
MAD2L1BP-encoded p31comet mediates Trip13-dependent disassembly of Mad2- and Rev7-containing complexes and, through this antagonism, promotes timely spindle assembly checkpoint (SAC) silencing, faithful chromosome segregation, insulin signaling, and homology-directed repair (HDR) of DNA double-strand breaks. We identified a homozygous MAD2L1BP nonsense variant, R253*, in 2 siblings with microcephaly, epileptic encephalopathy, and juvenile granulosa cell tumors of ovary and testis. Patient-derived cells exhibited high-grade mosaic variegated aneuploidy, slowed-down proliferation, and instability of truncated p31comet mRNA and protein. Corresponding recombinant p31comet was defective in Trip13, Mad2, and Rev7 binding and unable to support SAC silencing or HDR. Furthermore, C-terminal truncation abrogated an identified interaction of p31comet with tp53. Another homozygous truncation, R227*, detected in an early-deceased patient with low-level aneuploidy, severe epileptic encephalopathy, and frequent blood glucose elevations, likely corresponds to complete loss of function, as in Mad2l1bp-/- mice. Thus, human mutations of p31comet are linked to aneuploidy and tumor predisposition.
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Encefalopatías , Tumor de Células de la Granulosa , Neoplasias Ováricas , Femenino , Humanos , Animales , Ratones , Proteínas Mad2/genética , Proteínas Mad2/metabolismo , Tumor de Células de la Granulosa/genética , Mutación , AneuploidiaRESUMEN
Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders.
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Trastornos del Neurodesarrollo , Neurogénesis , Complejo Represivo Polycomb 2 , Animales , Embrión de Pollo , Humanos , Diferenciación Celular/genética , Núcleo Celular , Cromatina/genética , Metiltransferasas , Trastornos del Neurodesarrollo/genética , Neurogénesis/genética , Complejo Represivo Polycomb 2/genéticaRESUMEN
PURPOSE: Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified. METHODS: Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. RESULTS: In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect. CONCLUSION: HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome.
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Síndrome de Angelman , Trastornos del Neurodesarrollo , Humanos , Síndrome de Angelman/genética , Ubiquitina/genética , Ubiquitina-Proteína Ligasas/genética , Trastornos del Neurodesarrollo/genética , FenotipoRESUMEN
Pathogenic variants in GEMIN4 have recently been linked to an inherited autosomal recessive neurodevelopmental disorder characterized with microcephaly, cataracts, and renal abnormalities (NEDMCR syndrome). This report provides a retrospective review of 16 patients from 11 unrelated Saudi consanguineous families with GEMIN4 mutations. The cohort comprises 11 new and unpublished clinical details from five previously described patients. Only two missense, homozygous, pathogenic variants were found in all affected patients, suggesting a founder effect. All patients shared global developmental delay with variable ophthalmological, renal, and skeletal manifestations. In addition, we knocked down endogenous Drosophila GEMIN4 in neurons to further investigate the mechanism of the functional defects in affected patients. Our fly model findings demonstrated developmental defects and motor dysfunction suggesting that loss of GEMIN4 function is detrimental in vivo; likely similar to human patients. To date, this study presents the largest cohort of patients affected with GEMIN4 mutations. Considering that identifying GEMIN4 defects in patients presenting with neurodevelopmental delay and congenital cataract will help in early diagnosis, appropriate management and prevention plans that can be made for affected families.
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Anomalías Múltiples , Catarata , Microcefalia , Trastornos del Neurodesarrollo , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Catarata/patología , Homocigoto , Humanos , Riñón/anomalías , Microcefalia/diagnóstico , Microcefalia/genética , Microcefalia/patología , Antígenos de Histocompatibilidad Menor , Trastornos del Neurodesarrollo/genética , Linaje , Ribonucleoproteínas Nucleares Pequeñas/genética , Síndrome , Anomalías UrogenitalesRESUMEN
The eukaryotic CDC45/MCM2-7/GINS (CMG) helicase unwinds the DNA double helix during DNA replication. The GINS subcomplex is required for helicase activity and is, therefore, essential for DNA replication and cell viability. Here, we report the identification of 7 individuals from 5 unrelated families presenting with a Meier-Gorlin syndrome-like (MGS-like) phenotype associated with hypomorphic variants of GINS3, a gene not previously associated with this syndrome. We found that MGS-associated GINS3 variants affecting aspartic acid 24 (D24) compromised cell proliferation and caused accumulation of cells in S phase. These variants shortened the protein half-life, altered key protein interactions at the replisome, and negatively influenced DNA replication fork progression. Yeast expressing MGS-associated variants of PSF3 (the yeast GINS3 ortholog) also displayed impaired growth, S phase progression defects, and decreased Psf3 protein stability. We further showed that mouse embryos homozygous for a D24 variant presented intrauterine growth retardation and did not survive to birth, and that fibroblasts derived from these embryos displayed accelerated cellular senescence. Taken together, our findings implicate GINS3 in the pathogenesis of MGS and support the notion that hypomorphic variants identified in this gene impaired cell and organismal growth by compromising DNA replication.
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Micrognatismo , Saccharomyces cerevisiae , Animales , Proteínas Cromosómicas no Histona , Microtia Congénita , Replicación del ADN/genética , Trastornos del Crecimiento , Humanos , Ratones , Micrognatismo/genética , Proteínas de Mantenimiento de Minicromosoma/genética , Rótula/anomalíasRESUMEN
Heterozygous pathogenic variants in SLC12A2 are reported in patients with nonsyndromic hearing loss. Recently, homozygous loss-of-function variants have been reported in two patients with syndromic intellectual disability, with or without hearing loss. However, the clinical and molecular spectrum of SLC12A2 disease has yet to be characterized and confirmed. Using whole-exome sequencing, we detected a homozygous splicing variant in four patients from two independent families with severe developmental delay, microcephaly, respiratory abnormalities, and subtle dysmorphic features, with or without congenital hearing loss. We also reviewed the reported cases with pathogenic variants associated with autosomal dominant and recessive forms of the SLC12A2 disease. About 50% of the cases have syndromic and nonsyndromic congenital hearing loss. All patients harboring the recessive forms of the disease presented with severe global developmental delay. Interestingly, all reported variants are located in the c-terminal domain, suggesting a critical role of this domain for the proper function of the encoded co-transporter protein. In conclusion, our study provides an additional confirmation of the autosomal recessive SLC12A2 disease.
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Sordera/genética , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/genética , Miembro 2 de la Familia de Transportadores de Soluto 12/genética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Niño , Preescolar , Sordera/complicaciones , Sordera/diagnóstico por imagen , Sordera/patología , Exoma/genética , Femenino , Genes Recesivos/genética , Homocigoto , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/patología , Masculino , Mutación/genética , Linaje , Fenotipo , Empalme del ARN/genética , Miembro 2 de la Familia de Transportadores de Soluto 12/deficiencia , Secuenciación del ExomaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway-Ribosome-associated Quality Control (RQC)-by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF's role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration.
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Enfermedades Neuromusculares/metabolismo , Ribosomas/metabolismo , Secuencia de Aminoácidos , Animales , Femenino , Humanos , Masculino , Ratones , Ratones Noqueados , Mutación , Enfermedades Neuromusculares/genética , Enfermedades Neuromusculares/patología , Proteolisis , Proteínas de Unión al ARN/química , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Ribosomas/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Alineación de SecuenciaRESUMEN
PURPOSE: Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD. METHODS: We retrospectively collected the clinical and molecular information on 13 families with ASNSD from the major metabolic clinics in Saudi Arabia. RESULTS: The major phenotypes included congenital microcephaly (100%), facial dysmorphism (100%), global developmental delay (100%), brain abnormalities (100%), spasticity (86%), and infantile-onset seizures (93%). Additional unreported phenotypes included umbilical hernia, osteopenia, eczema, lung hypoplasia, and hearing loss. Overall, seven homozygous variants accounted for ASNSD. The p.Tyr398Cys and p.Asn75Ile variants accounted for 54% of the cases. The clinical sensitivity and specificity of the proposed biochemical analysis of cerebrospinal fluid (CSF) for the detection of patients with ASNSD were 83% and 98%, respectively. CONCLUSION: Our study describes the largest reported ASNSD cohort with clinical, molecular, and biochemical characterization. Taking into consideration the suboptimal sensitivity of biochemical screening, the delineation of the phenotype variant spectrum is of diagnostic utility for accurate diagnosis, prognosis, counseling, and carrier screening.
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Aspartatoamoníaco Ligasa , Discapacidad Intelectual , Microcefalia , Aspartatoamoníaco Ligasa/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Estudios Retrospectivos , Arabia Saudita/epidemiologíaRESUMEN
Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.
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Epilepsia/genética , Genes Recesivos , Mutación con Pérdida de Función/genética , Oxidorreductasas/genética , Uridina Difosfato Glucosa Deshidrogenasa/genética , Adolescente , Alelos , Animales , Niño , Preescolar , Femenino , Humanos , Lactante , Cinética , Masculino , Organoides/patología , Oxidorreductasas/química , Linaje , Dominios Proteicos , Síndrome , Pez CebraRESUMEN
BACKGROUND: Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of patients in a single genetic test. METHODS: In May 2013, we implemented exome sequencing in routine diagnostics for patients suffering from PIDs. This study reports the clinical utility and diagnostic yield for a heterogeneous group of 254 consecutively referred PID patients from 249 families. For the majority of patients, the clinical diagnosis was based on clinical criteria including rare and/or unusual severe bacterial, viral, or fungal infections, sometimes accompanied by autoimmune manifestations. Functional immune defects were interpreted in the context of aberrant immune cell populations, aberrant antibody levels, or combinations of these factors. RESULTS: For 62 patients (24%), exome sequencing identified pathogenic variants in well-established PID genes. An exome-wide analysis diagnosed 10 additional patients (4%), providing diagnoses for 72 patients (28%) from 68 families altogether. The genetic diagnosis directly indicated novel treatment options for 25 patients that received a diagnosis (34%). CONCLUSION: Exome sequencing as a first-tier test for PIDs granted a diagnosis for 28% of patients. Importantly, molecularly defined diagnoses indicated altered therapeutic options in 34% of cases. In addition, exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases, including in silico extension of existing gene lists and re-analysis of existing data.
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Secuenciación del Exoma/métodos , Pruebas Genéticas/métodos , Enfermedades de Inmunodeficiencia Primaria/genética , Adolescente , Adulto , Preescolar , Femenino , Pruebas Genéticas/normas , Humanos , Lactante , Masculino , Persona de Mediana Edad , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Sensibilidad y Especificidad , Secuenciación del Exoma/normasRESUMEN
BACKGROUND: Tetrahydrobiopterin is an essential cofactor for the hydroxylation of aromatic amino acids phenylalanine, tyrosine, and tryptophan. Therefore, tetrahydrobiopterin deficiency results in hyperphenylalaninemia as well as dopamine and serotonin depletion in the central nervous system. The enzyme 6-pyruvoyltetrahydropterin synthase catalyzes the second step of de novo synthesis of tetrahydrobiopterin, and its deficiency is the most frequent cause of tetrahydrobiopterin metabolism disorders. METHOD: We conducted a retrospective chart review of 28 subjects from 24 families with molecularly confirmed 6-pyruvoyltetrahydropterin synthase deficiency from six centers in three Arab countries. We reviewed clinical, biochemical, and molecular data. We also reviewed previously published cohorts of subjects with 6-pyruvoyltetrahydropterin synthase deficiency. RESULTS: Similar to previous observations, we show that early treatment (less than two months) is associated with better outcome. We identify eight PTS variants in 24 independent families. The most common variant is (c.238A>G; p.M80V) with an allele count of 33%. We also identify one novel variant (c.2T>G; p.?). CONCLUSION: The deficiency of 6-pyruvoyltetrahydropterin synthase is relatively common in the Arab population and should be considered in individuals with hyperphenylalaninemia. More natural history studies with comprehensive biochemical and molecular genetics data are needed for a robust base for the development of future therapy.
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Árabes , Consanguinidad , Fenilcetonurias , Liasas de Fósforo-Oxígeno/deficiencia , Adolescente , Árabes/genética , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Recién Nacido Pequeño para la Edad Gestacional , Masculino , Fenilcetonurias/tratamiento farmacológico , Fenilcetonurias/genética , Fenilcetonurias/metabolismo , Fenilcetonurias/fisiopatología , Liasas de Fósforo-Oxígeno/genética , Liasas de Fósforo-Oxígeno/metabolismo , Estudios RetrospectivosRESUMEN
An increasing number of mitochondrial diseases are found to be caused by pathogenic variants in nuclear encoded mitochondrial aminoacyl-tRNA synthetases. FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) which transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, a total of 21 subjects with FARS2 deficiency have been reported to date with a spectrum of disease severity that falls between two phenotypes; early onset epileptic encephalopathy and a less severe phenotype characterized by spastic paraplegia. In this report, we present an additional 15 individuals from 12 families who are mostly Arabs homozygous for the pathogenic variant Y144C, which is associated with the more severe early onset phenotype. The total number of unique pathogenic FARS2 variants known to date is 21 including three different partial gene deletions reported in four individuals. Except for the large deletions, all variants but two (one in-frame deletion of one amino acid and one splice-site variant) are missense. All large deletions and the single splice-site variant are in trans with a missense variant. This suggests that complete loss of function may be incompatible with life. In this report, we also review structural, functional, and evolutionary significance of select FARS2 pathogenic variants reported here.
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Aminoacil-ARNt Sintetasas/genética , Mitocondrias/genética , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , Fenilalanina-ARNt Ligasa/genética , Adolescente , Adulto , Aminoacil-ARNt Sintetasas/deficiencia , Niño , Preescolar , Femenino , Eliminación de Gen , Humanos , Masculino , Mitocondrias/enzimología , Mitocondrias/patología , Enfermedades Mitocondriales/enzimología , Enfermedades Mitocondriales/patología , Proteínas Mitocondriales/química , Proteínas Mitocondriales/deficiencia , Mutación/genética , Paraplejía/genética , Paraplejía/patología , Fenilalanina/genética , Fenilalanina/metabolismo , Fenilalanina-ARNt Ligasa/química , Fenilalanina-ARNt Ligasa/deficiencia , Isoformas de Proteínas/genética , Relación Estructura-Actividad , Adulto JovenRESUMEN
Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile-onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17-related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with nine novel MPV17 pathogenic variants. We summarize the clinical features of all 100 affected individuals and review the total 48 MPV17 pathogenic variants. The vast majority of affected individuals presented with an early-onset encephalohepatopathic disease characterized by hepatic and neurological manifestations, failure to thrive, lactic acidemia, and mtDNA depletion detected mainly in liver tissue. Rarely, MPV17 deficiency can cause a late-onset neuromyopathic disease characterized by myopathy and peripheral neuropathy with no or minimal liver involvement. Approximately half of the MPV17 pathogenic variants are missense. A genotype with biallelic missense variants, in particular homozygous p.R50Q, p.P98L, and p.R41Q, can carry a relatively better prognosis.
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ADN Mitocondrial/genética , Trastornos Heredodegenerativos del Sistema Nervioso , Hepatopatías , Proteínas de la Membrana/genética , Enfermedades Mitocondriales , Proteínas Mitocondriales/genética , Enfermedades del Sistema Nervioso Periférico , Trastornos Heredodegenerativos del Sistema Nervioso/diagnóstico , Trastornos Heredodegenerativos del Sistema Nervioso/genética , Trastornos Heredodegenerativos del Sistema Nervioso/metabolismo , Humanos , Hígado/metabolismo , Hepatopatías/diagnóstico , Hepatopatías/genética , Hepatopatías/metabolismo , Mitocondrias/genética , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Mutación , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/genética , Enfermedades del Sistema Nervioso Periférico/metabolismoRESUMEN
F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4-related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype-phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies.
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ADN Mitocondrial/genética , Proteínas F-Box/genética , Estudios de Asociación Genética , Encefalomiopatías Mitocondriales/genética , Ubiquitina-Proteína Ligasas/genética , Acidosis Láctica/genética , Cardiomiopatía Hipertrófica/genética , Predisposición Genética a la Enfermedad , Humanos , Estimación de Kaplan-Meier , Mitocondrias/genética , Encefalomiopatías Mitocondriales/epidemiología , Encefalomiopatías Mitocondriales/patología , Proteínas Mitocondriales/genética , Hipotonía Muscular/genética , Mutación , Fosforilación Oxidativa , Proteoma/genéticaRESUMEN
Deformed epidermal autoregulatory factor-1 (DEAF1), a transcription factor essential for central nervous system and early embryonic development, has recently been implicated in a series of intellectual disability-related neurodevelopmental anomalies termed, in this study, as DEAF1-associated neurodevelopmental disorder (DAND). We identified six potentially deleterious DEAF1 variants in a cohort of individuals with DAND via clinical exome sequencing (CES) and in silico analysis, including two novel de novo variants: missense variant c.634G > A p.Gly212Ser in the SAND domain and deletion variant c.913_915del p.Lys305del in the NLS domain, as well as c.676C > T p.Arg226Trp, c.700T > A p.Trp234Arg, c.737G > C p.Arg246Thr, and c.791A > C p.Gln264Pro. Luciferase reporter, immunofluorescence staining, and electrophoretic mobility shift assays revealed that these variants had decreased transcriptional repression activity at the DEAF1 promoter and reduced affinity to consensus DEAF1 DNA binding sequences. In addition, c.913_915del p.K305del localized primarily to the cytoplasm and interacted with wild-type DEAF1. Our results demonstrate that variants located within the SAND or NLS domains significantly reduce DEAF1 transcriptional regulatory activities and are thus, likely to contribute to the underlying clinical concerns in DAND patients. These findings illustrate the importance of experimental characterization of variants with uncertain significance identified by CES to assess their potential clinical significance and possible use in diagnosis.
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Exoma/genética , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Proteínas Nucleares/genética , Secuencia de Aminoácidos , Estudios de Cohortes , Proteínas de Unión al ADN , Humanos , Mutación , Proteínas Nucleares/metabolismo , Fenotipo , Regiones Promotoras Genéticas/genética , Alineación de Secuencia , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Secuenciación Completa del GenomaRESUMEN
Here we report the smallest deletion involving SNURF/SNRPN that causes major symptoms of Prader-Willi syndrome (PWS), including hypotonia, dysmorphic features, intellectual disability, and obesity. A female patient with the aforementioned and additional features was referred to the Mayo Clinic Cytogenetics laboratory for genetic testing. Chromosomal microarray analysis and subsequent Sanger sequencing identified a de novo 6.4 kb deletion at 15q11.2, containing exon 1 of the SNURF gene and exon 1 of the shortest isoform of the SNRPN gene. SNURF/SNRPN exon 1, which is methylated on the silent maternal allele, is associated with acetylated histones on the expressed paternal allele. This region also overlaps with the PWS-imprinting center (IC). Subsequent molecular methylation analysis was performed using methylation-specific MLPA (MS-MLPA), which characterized that the deletion of SNURF/SNRPN exon 1 was paternal in origin, consistent with the PWS-like phenotype. Since SNURF/SNRPN gene and the PWS-IC are known to regulate snoRNAs, it is likely that the PWS-like phenotype observed in patients with paternal SNURF/SNRPN deletion is due to the disrupted expression of SNORD116 snoRNAs.
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Exones , Eliminación de Gen , Proteínas Nucleares/genética , Fenotipo , Síndrome de Prader-Willi/genética , Niño , Metilación de ADN , Femenino , Impresión Genómica , Humanos , Síndrome de Prader-Willi/diagnóstico , ARN Nucleolar Pequeño/genéticaRESUMEN
BACKGROUND: Neurodevelopment is orchestrated by a wide range of genes, and the genetic causes of neurodevelopmental disorders are thus heterogeneous. We applied whole exome sequencing (WES) for molecular diagnosis and in silico analysis to identify novel disease gene candidates in a cohort from Saudi Arabia with primarily Mendelian neurologic diseases. METHODS: We performed WES in 31 mostly consanguineous Arab families and analyzed both single nucleotide and copy number variants (CNVs) from WES data. Interaction/expression network and pathway analyses, as well as paralog studies were utilized to investigate potential pathogenicity and disease association of novel candidate genes. Additional cases for candidate genes were identified through the clinical WES database at Baylor Miraca Genetics Laboratories and GeneMatcher. RESULTS: We found known pathogenic or novel variants in known disease genes with phenotypic expansion in 6 families, disease-associated CNVs in 2 families, and 12 novel disease gene candidates in 11 families, including KIF5B, GRM7, FOXP4, MLLT1, and KDM2B. Overall, a potential molecular diagnosis was provided by variants in known disease genes in 17 families (54.8 %) and by novel candidate disease genes in an additional 11 families, making the potential molecular diagnostic rate ~90 %. CONCLUSIONS: Molecular diagnostic rate from WES is improved by exome-predicted CNVs. Novel candidate disease gene discovery is facilitated by paralog studies and through the use of informatics tools and available databases to identify additional evidence for pathogenicity. TRIAL REGISTRATION: Not applicable.
Asunto(s)
Árabes/genética , Consanguinidad , Exoma/genética , Técnicas de Diagnóstico Molecular , Enfermedades del Sistema Nervioso/genética , Linaje , Análisis de Secuencia de ADN , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Minería de Datos , Bases de Datos Genéticas , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Enfermedades del Sistema Nervioso/diagnóstico , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
ADAT3-related intellectual disability has been recently described in 24 individuals from eight Saudi families who had cognitive impairment and strabismus. Other common features included growth failure, microcephaly, tone abnormalities, epilepsy, and nonspecific brain abnormalities. A single homozygous founder mutation (c.382G>A:p.(V128M)) in the ADAT3 gene, which encodes a protein that functions in tRNA editing, was identified in all affected individuals. In this report, we present additional 15 individuals from 11 families (10 Saudis and 1 Emirati) who are homozygous for the same founder mutation. In addition to the universal findings of intellectual disability and strabismus, the majority exhibited microcephaly and growth failure. Additional features not reported in the original cohort include dysmorphic facial features (prominent forehead, up-slanted palpebral fissures, epicanthus, and depressed nasal bridge), behavioral problems (hyperactivity and aggressiveness), recurrent otitis media, and growth hormone deficiency. ADAT3-related intellectual disability is an important recognizable cause of intellectual disability in Arabia.