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1.
Trends Genet ; 38(4): 321-324, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34696899

RESUMO

Maturity-onset diabetes in the young (MODY) comprises monogenic phenotypes of young-onset, insulinopenic diabetes. All its forms are dominantly inherited. Why? Are the pancreatic ß cells only harmed by heterozygous variants? We propose that recessive MODYs do exist but have escaped detection due to lack of family history suggestive of monogenic inheritance.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Diabetes Mellitus Tipo 2/genética , Humanos , Mutação , Fenótipo
2.
Mov Disord ; 39(2): 400-410, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38314870

RESUMO

BACKGROUND: Congenital mirror movements (CMM) is a rare neurodevelopmental disorder characterized by involuntary movements from one side of the body that mirror voluntary movements on the opposite side. To date, five genes have been associated with CMM, namely DCC, RAD51, NTN1, ARHGEF7, and DNAL4. OBJECTIVE: The aim of this study is to characterize the genetic landscape of CMM in a large group of 80 affected individuals. METHODS: We screened 80 individuals with CMM from 43 families for pathogenic variants in CMM genes. In large CMM families, we tested for presence of pathogenic variants in multiple affected and unaffected individuals. In addition, we evaluated the impact of three missense DCC variants on binding between DCC and Netrin-1 in vitro. RESULTS: Causal pathogenic/likely pathogenic variants were found in 35% of probands overall, and 70% with familial CMM. The most common causal gene was DCC, responsible for 28% of CMM probands and 80% of solved cases. RAD51, NTN1, and ARHGEF7 were rare causes of CMM, responsible for 2% each. Penetrance of CMM in DCC pathogenic variant carriers was 68% and higher in males than females (74% vs. 54%). The three tested missense variants (p.Ile164Thr; p.Asn176Ser; and p.Arg1343His) bind Netrin-1 similarly to wild type DCC. CONCLUSIONS: A genetic etiology can be identified in one third of CMM individuals, with DCC being the most common gene involved. Two thirds of CMM individuals were unsolved, highlighting that CMM is genetically heterogeneous and other CMM genes are yet to be discovered. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Discinesias , Transtornos dos Movimentos , Masculino , Feminino , Humanos , Netrina-1/genética , Receptor DCC/genética , Transtornos dos Movimentos/genética , Mutação de Sentido Incorreto/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética
3.
Hum Genet ; 142(7): 909-925, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37183190

RESUMO

Contactin-associated protein-like 2 (CNTNAP2) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell-cell adhesion and synaptic interactions. Biallelic CNTNAP2 loss has been associated with "Pitt-Hopkins-like syndrome-1" (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20) CNTNAP2 variants and carried out a literature review to characterize the genotype-phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype-phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (p < 0.0001), epilepsy (p < 0.0001), hyporeflexia (p = 0.012), ASD (p = 0.009), language impairment (p = 0.020) and severe cognitive impairment (p = 0.031) were significantly associated with the presence of biallelic versus monoallelic variants. We have defined the main features associated with biallelic CNTNAP2 variants, as severe cognitive impairment, epilepsy and behavioral abnormalities. We propose CASPR2-deficiency neurodevelopmental disorder as an exclusively recessive disease while the contribution of heterozygous variants is less likely to follow an autosomal dominant inheritance pattern.


Assuntos
Transtorno do Espectro Autista , Epilepsia , Humanos , Criança , Transtorno do Espectro Autista/genética , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Estudos de Associação Genética , Convulsões/genética , Contactinas/genética
4.
Am J Hum Genet ; 105(4): 854-868, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31585109

RESUMO

Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs∗4]; c.2564_2567dupTGTT [p.Leu856Phefs∗5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).


Assuntos
Axônios/patologia , Caderinas/genética , Corpo Caloso/patologia , Olho/patologia , Genitália/patologia , Cardiopatias Congênitas/genética , Transtornos do Neurodesenvolvimento/genética , Mutação da Fase de Leitura , Heterozigoto , Humanos , Transtornos do Neurodesenvolvimento/patologia
5.
Pediatr Dermatol ; 39(2): 281-287, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35178721

RESUMO

RHOA-related neuroectodermal syndrome is characterised by linear skin hypopigmentation along Blaschko's lines associated with alopecia, leukoencephalopathy, facial and limb hypoplasia, and ocular, dental, and acral anomalies. Herein, we report a patient with patterned cutaneous hypopigmentation with a similar phenotype due to a novel postzygotic RHOA variant (c.210G>T; p.Arg70Ser). This illustrates that the complexity of the orchestration of morphogenesis and organogenesis can be affected by different variants in the same gene.


Assuntos
Hipopigmentação , Mosaicismo , Humanos , Hipopigmentação/genética , Hipopigmentação/patologia , Fenótipo , Pele/patologia , Proteína rhoA de Ligação ao GTP/genética
6.
Hum Mutat ; 42(12): 1576-1583, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34570399

RESUMO

Aminoacyl-tRNA synthetases (aaRS) are ubiquitously expressed enzymes responsible for ligating amino acids to their cognate tRNA molecules through an aminoacylation reaction. The resulting aminoacyl-tRNA is delivered to ribosome elongation factors to participate in protein synthesis. Seryl-tRNA synthetase (SARS1) is one of the cytosolic aaRSs and catalyzes serine attachment to tRNASer . SARS1 deficiency has already been associated with moderate intellectual disability, ataxia, muscle weakness, and seizure in one family. We describe here a new clinical presentation including developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death, in a consanguineous Turkish family, with biallelic variants (c.638G>T, p.(Arg213Leu)) in SARS1. This missense variant was shown to lead to protein instability, resulting in reduced protein level and enzymatic activity. Our results describe a new clinical entity and expand the clinical and mutational spectrum of SARS1 and aaRS deficiencies.


Assuntos
Aminoacil-tRNA Sintetases , Cardiomiopatias , Surdez , Aminoacil-tRNA Sintetases/genética , Aminoacilação , Cardiomiopatias/genética , Criança , Surdez/genética , Humanos , Perda de Heterozigosidade
7.
Am J Hum Genet ; 102(3): 364-374, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29429573

RESUMO

Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.


Assuntos
Osso e Ossos/patologia , Colestase/genética , Diarreia/genética , Perda Auditiva/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação com Perda de Função/genética , Adolescente , Animais , Pré-Escolar , Diarreia/fisiopatologia , Família , Feminino , Fibroblastos/patologia , Motilidade Gastrointestinal , Humanos , Recém-Nascido , Linfócitos/patologia , Masculino , Linhagem , Fenótipo , Síndrome , Adulto Jovem , Peixe-Zebra
8.
Am J Hum Genet ; 103(5): 752-768, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388402

RESUMO

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.


Assuntos
Haploinsuficiência/genética , Deficiência Intelectual/genética , Megalencefalia/genética , Fatores de Transcrição NFI/genética , Adolescente , Adulto , Animais , Córtex Cerebral/patologia , Criança , Pré-Escolar , Códon sem Sentido/genética , Estudos de Coortes , Corpo Caloso/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
9.
Am J Hum Genet ; 102(5): 995-1007, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29656858

RESUMO

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.


Assuntos
Doenças Cerebelares/genética , Epilepsia Generalizada/genética , Fácies , Mutação de Sentido Incorreto/genética , Proteínas de Transporte Vesicular/genética , Idade de Início , Pré-Escolar , Feminino , Heterozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo
10.
Genet Med ; 23(8): 1484-1491, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33833411

RESUMO

PURPOSE: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. METHODS: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies. RESULTS: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI. CONCLUSION: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex.


Assuntos
Hipopigmentação , Megalencefalia , Humanos , Hipopigmentação/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Mosaicismo , Fenótipo , Serina-Treonina Quinases TOR/genética
11.
J Med Genet ; 57(12): 808-819, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32409512

RESUMO

INTRODUCTION: Pigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko's lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 (TFE3) have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions. MATERIALS AND METHODS: Subsequent data sharing allowed the clustering of de novo TFE3 variants identified by exome sequencing on DNA extracted from leucocytes in patients referred for syndromic ID with or without PM. RESULTS: We describe the detailed clinical and molecular data of 17 individuals harbouring a de novo TFE3 variant, including the patients that initially allowed reporting TFE3 as a new disease-causing gene. The 12 females and 5 males presented with pigmentation anomalies on Blaschko's lines, severe ID, epilepsy, storage disorder-like features, growth retardation and recognisable facial dysmorphism. The variant was at a mosaic state in at least two male patients. All variants were missense except one splice variant. Eleven of the 13 variants were localised in exon 4, 2 in exon 3, and 3 were recurrent variants. CONCLUSION: This series further delineates the specific storage disorder-like phenotype with PM ascribed to de novo TFE3 mutation in exons 3 and 4. It confirms the identification of a novel X-linked human condition associated with mosaicism and dysregulation within the mechanistic target of rapamycin (mTOR) pathway, as well as a link between lysosomal signalling and human development.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Epilepsia/genética , Deficiência Intelectual/genética , Transtornos da Pigmentação/genética , Adolescente , Adulto , Criança , Pré-Escolar , Epilepsia/complicações , Epilepsia/patologia , Feminino , Genes Ligados ao Cromossomo X/genética , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/patologia , Masculino , Mosaicismo , Patologia Molecular/normas , Transtornos da Pigmentação/complicações , Transtornos da Pigmentação/patologia , Sequenciamento do Exoma , Adulto Jovem
12.
Am J Hum Genet ; 101(3): 369-390, 2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28867142

RESUMO

Genetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. By leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection, we systematically evaluated the potential role of PMMs in autism risk. Initial re-evaluation of published single-nucleotide variant (SNV) de novo mutations showed evidence consistent with putative PMMs for 11% of mutations. We developed a robust and sensitive SNV PMM calling approach integrating complementary callers, logistic regression modeling, and additional heuristics. In our high-confidence call set, we identified 470 PMMs in children, increasing the proportion of mosaic SNVs to 22%. Probands have a significant burden of synonymous PMMs and these mutations are enriched for computationally predicted impacts on splicing. Evidence of increased missense PMM burden was not seen in the full cohort. However, missense burden signal increased in subcohorts of families where probands lacked nonsynonymous germline mutations, especially in genes intolerant to mutations. Parental mosaic mutations that were transmitted account for 6.8% of the presumed de novo mutations in the children. PMMs were identified in previously implicated high-confidence neurodevelopmental disorder risk genes, such as CHD2, CTNNB1, SCN2A, and SYNGAP1, as well as candidate risk genes with predicted functions in chromatin remodeling or neurodevelopment, including ACTL6B, BAZ2B, COL5A3, SSRP1, and UNC79. We estimate that PMMs potentially contribute risk to 3%-4% of simplex ASD case subjects and future studies of PMMs in ASD and related disorders are warranted.


Assuntos
Transtorno do Espectro Autista/genética , Éxons/genética , Predisposição Genética para Doença , Variação Genética , Mosaicismo , Mutação , Transtorno do Espectro Autista/patologia , Criança , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Humanos , Masculino , Zigoto
13.
Genet Med ; 22(2): 432-436, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31462756

RESUMO

PURPOSE: Our laboratory has classified patients with methylmalonic aciduria using somatic cell studies for over four decades. We have accumulated 127 fibroblast lines from patients with persistent elevated methylmalonic acid (MMA) levels in which no genetic cause could be identified. Cultured fibroblasts from 26 of these patients had low [14C]propionate incorporation into macromolecules, possibly reflecting decreased methylmalonyl-CoA mutase function. METHODS: Genome sequencing (GS), copy-number variation (CNV) analysis, and RNA sequencing were performed on genomic DNA and complementary DNA (cDNA) from these 26 patients. RESULTS: No patient had two pathogenic variants in any gene associated with cobalamin metabolism. Nine patients had heterozygous variants of unknown significance previously identified by a next-generation sequencing (NGS) panel targeting cobalamin metabolic genes. Three patients had pathogenic changes in genes not associated with cobalamin metabolism (PCCA, EPCAM, and a 17q12 duplication) that explain parts of their phenotypes other than elevated MMA. CONCLUSION: Genome and RNA sequencing did not detect any additional putative causal genetic defects in known cobalamin genes following somatic cell studies and the use of a targeted NGS panel. They did detect pathogenic variants in other genes in three patients that explained some aspects of their clinical presentation.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Ácido Metilmalônico/metabolismo , Vitamina B 12/genética , Sequência de Bases/genética , Linhagem Celular , Feminino , Fibroblastos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Metilmalonil-CoA Mutase/genética , Metilmalonil-CoA Mutase/metabolismo , Mutação/genética , Análise de Sequência de RNA/métodos , Vitamina B 12/metabolismo , Sequenciamento do Exoma/métodos
14.
Genet Med ; 22(7): 1280, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32483295

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

15.
Genet Med ; 22(3): 547-556, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31649276

RESUMO

PURPOSE: Treacher Collins syndrome (TCS) is a rare autosomal dominant mandibulofacial dysostosis, with a prevalence of 0.2-1/10,000. Features include bilateral and symmetrical malar and mandibular hypoplasia and facial abnormalities due to abnormal neural crest cell (NCC) migration and differentiation. To date, three genes have been identified: TCOF1, POLR1C, and POLR1D. Despite a large number of patients with a molecular diagnosis, some remain without a known genetic anomaly. METHODS: We performed exome sequencing for four individuals with TCS but who were negative for pathogenic variants in the known causative genes. The effect of the pathogenic variants was investigated in zebrafish. RESULTS: We identified three novel pathogenic variants in POLR1B. Knockdown of polr1b in zebrafish induced an abnormal craniofacial phenotype mimicking TCS that was associated with altered ribosomal gene expression, massive p53-associated cellular apoptosis in the neuroepithelium, and reduced number of NCC derivatives. CONCLUSION: Pathogenic variants in the RNA polymerase I subunit POLR1B might induce massive p53-dependent apoptosis in a restricted neuroepithelium area, altering NCC migration and causing cranioskeletal malformations. We identify POLR1B as a new causative gene responsible for a novel TCS syndrome (TCS4) and establish a novel experimental model in zebrafish to study POLR1B-related TCS.


Assuntos
Anormalidades Craniofaciais/genética , RNA Polimerases Dirigidas por DNA/genética , Disostose Mandibulofacial/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Animais , Apoptose/genética , Diferenciação Celular/genética , Movimento Celular/genética , Anormalidades Craniofaciais/patologia , Predisposição Genética para Doença , Humanos , Disostose Mandibulofacial/patologia , Mutação , Crista Neural/anormalidades , Crista Neural/patologia , Proteína Supressora de Tumor p53/genética , Sequenciamento do Exoma , Peixe-Zebra/genética
16.
J Genet Couns ; 29(6): 1173-1185, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32302469

RESUMO

Tay-Sachs disease (TSD) is a hereditary neurodegenerative condition inherited through an autosomal recessive pattern. The incidence and carrier frequency of infantile TSD were found to be increased among French Canadians in specific areas of the province of Quebec or calculated from New England populations with French-Canadian heritage. No accurate infantile TSD carrier frequency for the whole French-Canadian population in Quebec has been published. In this study, we estimate the incidence and carrier frequency of infantile TSD in the Quebec French-Canadian population. The number of TSD cases was ascertained during the 1992-2015 period, as well as the number of births to mothers whose language of use is French. Seven cases of TSD have been diagnosed in Quebec during the period of ascertainment. This corresponds to an incidence of 1/218,144, which in turn corresponds to a carrier frequency of 1/234. In the same 24-year period, there are two French-Canadian couples who had a fetus prenatally diagnosed with TSD. If these cases are included, the incidence of TSD in the French-Canadian population of Quebec is 1/169,668 and the carrier frequency 1/206. These findings can be used for genetic counseling and policy decisions regarding carrier screening for TSD in populations of French-Canadian descent.


Assuntos
Triagem de Portadores Genéticos , Doença de Tay-Sachs/epidemiologia , Doença de Tay-Sachs/genética , Humanos , Incidência , Quebeque/epidemiologia , Estudos Retrospectivos , Doença de Tay-Sachs/diagnóstico
17.
Hum Mutat ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646703

RESUMO

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved.

18.
Neurogenetics ; 20(2): 103-108, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30924036

RESUMO

Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) is a non-catalytic component of the multi-tRNA synthetase complex which catalyzes the ligation of amino acids to the correct tRNAs. Pathogenic variants in several aminoacyl-tRNA synthetases genes have been linked to various neurological disorders, including leukodystrophies and pontocerebellar hypoplasias (PCH). To date, loss-of-function variants in AIMP1 have been associated with hypomyelinating leukodystrophy-3 (MIM 260600). Here, we report a novel frameshift AIMP1 homozygous variant (c.160delA,p.Lys54Asnfs) in a child with pontocerebellar hypoplasia and simplified gyral pattern, a phenotype not been previously described with AIMP1 variants, thus expanding the phenotypic spectrum. AIMP1 should be included in diagnostic PCH gene panels.


Assuntos
Doenças Cerebelares/genética , Citocinas/genética , Predisposição Genética para Doença , Proteínas de Neoplasias/genética , Doença de Pelizaeus-Merzbacher/genética , Proteínas de Ligação a RNA/genética , Citosol/metabolismo , Evolução Fatal , Mutação da Fase de Leitura , Deleção de Genes , Heterozigoto , Homozigoto , Humanos , Lactente , Masculino , Mitocôndrias/metabolismo , Bainha de Mielina/metabolismo , Fenótipo , Biossíntese de Proteínas , Desnaturação Proteica , Dobramento de Proteína , Isoformas de Proteínas
19.
Am J Hum Genet ; 99(6): 1368-1376, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27889060

RESUMO

Early-onset epileptic encephalopathy (EOEE) represents a heterogeneous group of severe disorders characterized by seizures, interictal epileptiform activity with a disorganized electroencephalography background, developmental regression or retardation, and onset before 1 year of age. Among a cohort of 57 individuals with epileptic encephalopathy, we ascertained two unrelated affected individuals with EOEE associated with developmental impairment and autosomal-recessive variants in AP3B2 by means of whole-exome sequencing. The targeted sequencing of AP3B2 in 86 unrelated individuals with EOEE led to the identification of an additional family. We gathered five additional families with eight affected individuals through the Matchmaker Exchange initiative by matching autosomal-recessive mutations in AP3B2. Reverse phenotyping of 12 affected individuals from eight families revealed a homogeneous EOEE phenotype characterized by severe developmental delay, poor visual contact with optic atrophy, and postnatal microcephaly. No spasticity, albinism, or hematological symptoms were reported. AP3B2 encodes the neuron-specific subunit of the AP-3 complex. Autosomal-recessive variations of AP3B1, the ubiquitous isoform, cause Hermansky-Pudlak syndrome type 2. The only isoform for the δ subunit of the AP-3 complex is encoded by AP3D1. Autosomal-recessive mutations in AP3D1 cause a severe disorder cumulating the symptoms of the AP3B1 and AP3B2 defects.


Assuntos
Complexo 3 de Proteínas Adaptadoras/genética , Subunidades beta do Complexo de Proteínas Adaptadoras/genética , Epilepsia/complicações , Epilepsia/genética , Genes Recessivos/genética , Mutação , Atrofia Óptica/complicações , Atrofia Óptica/genética , Idade de Início , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/genética , Linhagem , Síndrome
20.
PLoS Biol ; 14(3): e1002416, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26982032

RESUMO

Cilia have a unique diffusion barrier ("gate") within their proximal region, termed transition zone (TZ), that compartmentalises signalling proteins within the organelle. The TZ is known to harbour two functional modules/complexes (Meckel syndrome [MKS] and Nephronophthisis [NPHP]) defined by genetic interaction, interdependent protein localisation (hierarchy), and proteomic studies. However, the composition and molecular organisation of these modules and their links to human ciliary disease are not completely understood. Here, we reveal Caenorhabditis elegans CEP-290 (mammalian Cep290/Mks4/Nphp6 orthologue) as a central assembly factor that is specific for established MKS module components and depends on the coiled coil region of MKS-5 (Rpgrip1L/Rpgrip1) for TZ localisation. Consistent with a critical role in ciliary gate function, CEP-290 prevents inappropriate entry of membrane-associated proteins into cilia and keeps ARL-13 (Arl13b) from leaking out of cilia via the TZ. We identify a novel MKS module component, TMEM-218 (Tmem218), that requires CEP-290 and other MKS module components for TZ localisation and functions together with the NPHP module to facilitate ciliogenesis. We show that TZ localisation of TMEM-138 (Tmem138) and CDKL-1 (Cdkl1/Cdkl2/Cdkl3/Cdlk4 related), not previously linked to a specific TZ module, similarly depends on CEP-290; surprisingly, neither TMEM-138 or CDKL-1 exhibit interdependent localisation or genetic interactions with core MKS or NPHP module components, suggesting they are part of a distinct, CEP-290-associated module. Lastly, we show that families presenting with Oral-Facial-Digital syndrome type 6 (OFD6) have likely pathogenic mutations in CEP-290-dependent TZ proteins, namely Tmem17, Tmem138, and Tmem231. Notably, patient fibroblasts harbouring mutated Tmem17, a protein not yet ciliopathy-associated, display ciliogenesis defects. Together, our findings expand the repertoire of MKS module-associated proteins--including the previously uncharacterised mammalian Tmem80--and suggest an MKS-5 and CEP-290-dependent assembly pathway for building a functional TZ.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Cílios/fisiologia , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Sequência de Aminoácidos , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Quinases Ciclina-Dependentes/metabolismo , Humanos , Proteínas de Membrana/genética , Dados de Sequência Molecular , Síndromes Orofaciodigitais/genética
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