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1.
Am J Med Genet A ; 194(6): e63533, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38234231

RESUMO

Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra-rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44). Myopathy with elevated serum creatine kinase levels (346-3325 IU/L) affected all of them (38/38). 39% had scoliosis (10/26) and 57% had atlantoaxial instability (8/14). Cardiac arrhythmias were detected in 57% (20/35) and 46% had ventricular tachycardia (16/35). Congenital pyloric stenosis was diagnosed in 39% (18/46), 9 had esophageal dysmotility and 19 had intestinal dysmotility. Four patients suffered from intestinal perforations. Seven patients died at mean age of 17 years (range: 2 months to 39 years). The cause of death in four patients was cardiac arrhythmia and sudden death, while others died of prematurity, gastrointestinal perforation, and infected foot ulcers leading to sepsis. Our study highlights high prevalence of myopathy, metabolic abnormalities, cardiac, and gastrointestinal problems in patients with CGL4. CGL4 patients are at high risk of early death mainly caused by cardiac arrhythmias.


Assuntos
Lipodistrofia Generalizada Congênita , Proteínas de Ligação a RNA , Humanos , Masculino , Feminino , Lipodistrofia Generalizada Congênita/genética , Lipodistrofia Generalizada Congênita/complicações , Lipodistrofia Generalizada Congênita/patologia , Adolescente , Criança , Lactente , Pré-Escolar , Adulto , Adulto Jovem , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Hipertrigliceridemia/genética , Hipertrigliceridemia/complicações , Hipertrigliceridemia/patologia
2.
Clin Genet ; 101(2): 247-254, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34708404

RESUMO

Biallelic changes in the ZNFX1 gene have been recently reported to cause severe familial immunodeficiency. Through a search of our bio/databank with information from genetic testing of >55 000 individuals, we identified nine additional patients from seven families with six novel homozygous ZNFX1 variants. Consistent with the previously described phenotype, our patients suffered from monocytosis, thrombocytopenia, hepatosplenomegaly, recurrent infections, and lymphadenopathy. The two most severely affected probands also had renal involvement and clinical presentations compatible with hemophagocytic lymphohistiocytosis. The disease was less lethal among our patients than previously reported. We identified two missense changes, two variants predicted to result in complete protein loss through nonsense-mediated decay, and two frameshift changes that likely introduce a truncation. Our findings (i) independently confirm the role of ZNFX1 in primary genetic immunodeficiency, (ii) expand the genetic and clinical spectrum of ZNFX1-related disease, and (iii) illustrate the utility of large, well-curated, and continually updated genotype-phenotype databases in resolving molecular diagnoses of patients with initially negative genetic testing findings.


Assuntos
Alelos , Antígenos de Neoplasias/genética , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/genética , Mutação , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/genética , Mapeamento Cromossômico , Biologia Computacional/métodos , Análise Mutacional de DNA , Bases de Dados Genéticas , Fácies , Estudos de Associação Genética , Predisposição Genética para Doença , Homozigoto , Humanos , Linhagem , Fenótipo
3.
Brain ; 142(10): 2948-2964, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31501903

RESUMO

Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.


Assuntos
Moléculas de Adesão Celular/genética , Doenças Desmielinizantes/genética , Fatores de Crescimento Neural/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Adulto , Alelos , Axônios/metabolismo , Moléculas de Adesão Celular/metabolismo , Criança , Pré-Escolar , Doenças Desmielinizantes/metabolismo , Feminino , Frequência do Gene/genética , Humanos , Lactente , Masculino , Mutação , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Fibras Nervosas Mielinizadas/fisiologia , Fatores de Crescimento Neural/metabolismo , Malformações do Sistema Nervoso , Transtornos do Neurodesenvolvimento/metabolismo , Neuroglia/metabolismo , Linhagem , Nervos Periféricos , Isoformas de Proteínas/metabolismo , Nós Neurofibrosos/genética , Nós Neurofibrosos/metabolismo
5.
Genet Med ; 20(12): 1609-1616, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29620724

RESUMO

PURPOSE: To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized. METHODS: Detailed phenotyping and next-generation sequencing (panel and exome). RESULTS: Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average. CONCLUSION: By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.


Assuntos
Exoma/genética , Heterogeneidade Genética , Predisposição Genética para Doença , Anormalidades Musculoesqueléticas/genética , Alelos , Proteínas Sanguíneas/genética , Hidrolases de Éster Carboxílico , Estudos de Coortes , Exorribonucleases/genética , Feminino , Proteínas Fetais/genética , Efeito Fundador , Genética Populacional , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Membrana/genética , Anormalidades Musculoesqueléticas/classificação , Anormalidades Musculoesqueléticas/patologia , Proteínas de Neoplasias/genética , Proteínas Oncogênicas/genética , Fenótipo , Receptores de Superfície Celular/genética , Proteína Wnt3A/genética
6.
Hum Genet ; 136(11-12): 1419-1429, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28940097

RESUMO

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.


Assuntos
Exoma/genética , Heterogeneidade Genética , Marcadores Genéticos , Deficiência Intelectual/genética , Mutação , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Linhagem , Conformação Proteica
8.
J Med Genet ; 49(10): 630-5, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23054245

RESUMO

BACKGROUND: Osteogenesis imperfecta (OI) is an hereditary bone disease in which increased bone fragility leads to frequent fractures and other complications, usually in an autosomal dominant fashion. An expanding list of genes that encode proteins related to collagen metabolism are now recognised as important causes of autosomal recessive (AR) OI. Our aim was to study the contribution of known genes to AR OI in order to identify novel loci in mutation-negative cases. METHODS: We enrolled multiplex consanguineous families and simplex cases (also consanguineous) in which mutations in COL1A1 and COL1A2 had been excluded. We used autozygome guided mutation analysis of AR OI (AR OI) genes followed by exome sequencing when such analysis failed to identify the causative mutation. RESULTS: Two simplex and 11 multiplex families were enrolled, encompassing 27 cases. In three multiplex families, autozygosity and linkage analysis revealed a novel recessive OI locus on chromosome 9q31.1-31.3, and a novel truncating deletion of exon 4 of TMEM38B was identified within that interval. In addition, gonadal or gonadal/somatic mosaic mutations in COL1A1 or COL1A2 and homozygous mutations in recently described AR OI genes were identified in all remaining families. CONCLUSIONS: TMEM38B is a novel candidate gene for AR OI. Future studies are needed to explore fully the contribution of this gene to AR OI in other populations.


Assuntos
Genes Recessivos , Canais Iônicos/genética , Mutação , Osteogênese Imperfeita/genética , Arábia , Sequência de Bases , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Consanguinidade , Éxons , Feminino , Ordem dos Genes , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Osteogênese Imperfeita/diagnóstico
9.
Nat Genet ; 43(12): 1186-8, 2011 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-22019780

RESUMO

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that causes substantial morbidity. As is typical for many other multifactorial disorders, much of the heritability of SLE remains unknown. We identified a rare autosomal recessive form of SLE, in which autozygome analysis revealed a null mutation in the DNASE1L3 gene. The DNASE1L3-related SLE we describe was always pediatric in onset and correlated with a high frequency of lupus nephritis. Our findings confirm the critical role of impaired clearance of degraded DNA in SLE pathogenesis.


Assuntos
Endodesoxirribonucleases/genética , Lúpus Eritematoso Sistêmico/genética , Deleção de Sequência , Adolescente , Criança , Pré-Escolar , Consanguinidade , Feminino , Estudos de Associação Genética , Hereditariedade , Homozigoto , Humanos , Escore Lod , Masculino , Adulto Jovem
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