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1.
Am J Hum Genet ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31587868

RESUMO

NKAP is a ubiquitously expressed nucleoplasmic protein that is currently known as a transcriptional regulatory molecule via its interaction with HDAC3 and spliceosomal proteins. Here, we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP. These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins. Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects. The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis. In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers. These observations indicate the critical role of NKAP in transcriptional regulation and demonstrate that perturbations of the C-terminal region lead to developmental defects in both humans and zebrafish.

2.
Brain Dev ; 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540749

RESUMO

COL4A1-related disorder is recognized as a systemic disease because the alpha 1 chain of type IV collagen, encoded by COL4A1, is essential for basement membrane stability. However, muscular manifestations related to this disorder are rarely reported. We report the case of a 2-year-old boy with porencephaly, who harbored a de novo COL4A1 mutation of c.1853G > A, p. (Gly618Glu) and exhibited recurrent rhabdomyolysis with viral or bacterial infections. Moreover, he developed obstructive hypertrophic cardiomyopathy which required surgical intervention. Skeletal muscle biopsy revealed findings compatible with fiber-type disproportion. Ultrastructural study demonstrated the similar findings previously reported in mice with Col4a1 mutation including collagen disarray and reduction of electron density in the basement membrane of capillary endothelial cells and muscle fibers. Dilated endoplasmic reticulum in the capillary endothelial cells is also noted. This report adds another disease spectrum of COL4A1 mutation which include porencephaly, hypertrophic cardiomyopathy, rhabdomyolysis and fiber-type disproportion.

3.
Biol Pharm Bull ; 42(9): 1596-1599, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474720

RESUMO

Joint hypermobility syndrome (JHS) (also termed hypermobility type Ehlers-Danlos syndrome, hEDS) is a heritable connective tissue disorder that is characterized by generalized joint hypermobility, chronic pain, fatigue, and minor skin changes. Initially, it was reported that there is a small subset of patients with JHS/hEDS who have haploinsufficiency of tenascin-X (TNX). However, the relationship between TNXB and JHS/hEDS has not been reported at all afterwards. EDS was reclassified into thirteen types in 2017, and the causative gene of JHS/hEDS remained to be identified. Therefore, in this study in order to determine whether JHS/hEDS can be diagnosed by the concentrations of serum form of TNX (sTNX), we measured the concentrations of sTNX in 17 JHS/hEDS patients. The sTNX concentrations in half of the JHS/hEDS patients were significantly lower than those in healthy individuals. No mutations, insertions or deletions were detected in the TNX exon sequence of the JHS/hEDS patients except for one in patient. That patient has a heterozygous mutation. A correlation between sTNX concentration and mutation of the TNXB genomic sequence was not found in the JHS/hEDS patients. These results indicate that the decrease in sTNX concentration could be used as a risk factor for JHS/hEDS.

5.
J Hum Genet ; 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31558760

RESUMO

During the past decade, the search for pathogenic mutations in rare human genetic diseases has involved huge efforts to sequence coding regions, or the entire genome, using massively parallel short-read sequencers. However, the approximate current diagnostic rate is <50% using these approaches, and there remain many rare genetic diseases with unknown cause. There may be many reasons for this, but one plausible explanation is that the responsible mutations are in regions of the genome that are difficult to sequence using conventional technologies (e.g., tandem-repeat expansion or complex chromosomal structural aberrations). Despite the drawbacks of high cost and a shortage of standard analytical methods, several studies have analyzed pathogenic changes in the genome using long-read sequencers. The results of these studies provide hope that further application of long-read sequencers to identify the causative mutations in unsolved genetic diseases may expand our understanding of the human genome and diseases. Such approaches may also be applied to molecular diagnosis and therapeutic strategies for patients with genetic diseases in the future.

6.
Eur J Med Genet ; : 103769, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31536832

RESUMO

Mutations in methyl-CpG-binding protein 2 (MECP2) in males can lead to various phenotypes, ranging from neonatal encephalopathy to intellectual disability. In this study, using Nord's method of next-generation sequencing in three siblings, we identified a 0.6 kb deletion involving the transcriptional repression domain (TRD). Two males and one female had intellectual disability and apnea, but none met the criteria of Rett syndrome. Both males had sick sinus syndrome and severe tracheomalacia that resulted in early death. The mother, with skewed X-inactivation, had no symptoms. Therefore, this mutation is pathological for both males and females, resulting in sick sinus syndrome and severe tracheomalacia with strong reproducibility in males. Deletions involving major domains in MECP2 can result in a severe phenotype, and deletion of the TRD domain can cause severe autonomic nervous system dysregulation in males in these cases.

7.
Ann Neurol ; 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31433517

RESUMO

Leukoencephalopathies comprise a broad spectrum of disorders, but the genetic background of adult leukoencephalopathies has rarely been assessed. In this study, we analyzed 101 Japanese patients with genetically unresolved adult leukoencephalopathy using whole-exome sequencing and repeat-primed PCR for detecting GGC expansion in NOTCH2NLC. NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease. We found 12 patients with GGC expansion in NOTCH2NLC as the most frequent cause of adult leukoencephalopathy followed by NOTCH3 variants in our cohort. Further, we found one case with de novo GGC expansion, which might explain the underlying pathogenesis of sporadic cases. This article is protected by copyright. All rights reserved.

8.
J Hum Genet ; 64(11): 1107-1116, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31409854

RESUMO

The recent advent of long-read sequencing technologies is expected to provide reasonable answers to genetic challenges unresolvable by short-read sequencing, primarily the inability to accurately study structural variations, copy number variations, and homologous repeats in complex parts of the genome. However, long-read sequencing comes along with higher rates of random short deletions and insertions, and single nucleotide errors. The relatively higher sequencing accuracy of short-read sequencing has kept it as the first choice of screening for single nucleotide variants and short deletions and insertions. Albeit, short-read sequencing still suffers from systematic errors that tend to occur at specific positions where a high depth of reads is not always capable to correct for these errors. In this study, we compared the genotyping of mitochondrial DNA variants in three samples using PacBio's Sequel (Pacific Biosciences Inc., Menlo Park, CA, USA) long-read sequencing and illumina's HiSeqX10 (illumine Inc., San Diego, CA, USA) short-read sequencing data. We concluded that, despite the differences in the type and frequency of errors in the long-reads sequencing, its accuracy is still comparable to that of short-reads for genotyping short nuclear variants; due to the randomness of errors in long reads, a lower coverage, around 37 reads, can be sufficient to correct for these random errors.

9.
PLoS One ; 14(8): e0221482, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31430354

RESUMO

There have been increasing number of reports of SZT2-related neurological diseases, the main symptoms of which are epilepsy, developmental delay, macrocephaly and a dysmorphic corpus callosum. SZT2 functions as a regulator of mechanistic target of rapamycin complex 1 (mTORC1) signaling in cultured human cell lines and mouse tissues. However, it remains to be determined whether mutations in SZT2 in human patients alter mTORC1 signaling. In this study, we aimed to investigate the functional consequence of biallelic SZT2 variants in Epstein-Barr virus-induced lymphoblastoid cell lines (LCLs) established from two patients with a typical SZT2-related neurodevelopmental disease. Increased phosphorylation of S6 kinase and S6 was identified in patient-derived cell lines under amino acid-starved condition, suggestive of constitutive hyperactivation of mTORC1 signaling. This result was validated by constitutive lysosomal localization of mTOR in patients' LCLs. Furthermore, patients' LCLs display an excessive response to slight amino acid stimulation. Our data suggest the loss-of-function nature of SZT2 mutations in the patients, and consequent hyperactivation of mTORC1 signaling in response to both amino acid starvation and stimulation in their LCLs. By these functional analyses, the pathogenicity of newly identified SZT2 variants can be determined, allowing for more detailed characterization of genotype-phenotype correlations.

10.
Brain Dev ; 2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31288946

RESUMO

INTRODUCTION: A loss-of-function mutation in CACNA1A, which encodes P/Q-type Ca channels, causes various diseases. As most of the Ca channels at neuromuscular junctions are of the P/Q type, patients with loss-of-function CACNA1A mutations exhibit disturbed neuromuscular transmission. The associated jitters and blocking in such patients can be detected by single-fiber electromyography (SFEMG). CASES: We report two cases with different phenotypes, which were predicted to harbor loss-of-function mutations of CACNA1A, by using axonal stimulation SFEMG. One case involved a 2-year-old boy with episodic ataxia type 2. The other case involved a 7-year-old girl diagnosed with epileptic encephalopathy. SFEMG results revealed jitters and blocking in both cases. Moreover, whole exome sequencing (WES) revealed a heterozygous CACNA1A mutation, c.5251C>T, p.Arg1751Trp, in the former case and a novel de novo CACNA1A mutation, c.2122G>A, p.Val708Met, in the latter. CONCLUSIONS: Our cases indicate that SFEMG is a potentially useful diagnostic tool for patients with CACNA1A mutation, especially in pediatric cases where trio analysis is difficult or novel mutations are present.

11.
Genet Med ; 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31263216

RESUMO

PURPOSE: We observed four individuals in two unrelated but consanguineous families from Portugal and Brazil affected by early-onset retinal degeneration, sensorineural hearing loss, microcephaly, intellectual disability, and skeletal dysplasia with scoliosis and short stature. The phenotype precisely matched that of an individual of Azorean descent published in 1986 by Liberfarb and coworkers. METHODS: Patients underwent specialized clinical examinations (including ophthalmological, audiological, orthopedic, radiological, and developmental assessment). Exome and targeted sequencing was performed on selected individuals. Minigene constructs were assessed by quantitative polymerase chain reaction (qPCR) and Sanger sequencing. RESULTS: Affected individuals shared a 3.36-Mb region of autozygosity on chromosome 22q12.2, including a 10-bp deletion (NM_014338.3:c.904-12_904-3delCTATCACCAC), immediately upstream of the last exon of the PISD (phosphatidylserine decarboxylase) gene. Sequencing of PISD from paraffin-embedded tissue from the 1986 case revealed the identical homozygous variant. In HEK293T cells, this variant led to aberrant splicing of PISD transcripts. CONCLUSION: We have identified the genetic etiology of the Liberfarb syndrome, affecting brain, eye, ear, bone, and connective tissue. Our work documents the migration of a rare Portuguese founder variant to two continents and highlights the link between phospholipid metabolism and bone formation, sensory defects, and cerebral development, while raising the possibility of therapeutic phospholipid replacement.

12.
J Hum Genet ; 64(10): 1005-1014, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31311986

RESUMO

Complex rearrangements of chromosomes 3 and 9 were found in a patient presenting with severe epilepsy, developmental delay, dysmorphic facial features, and skeletal abnormalities. Molecular cytogenetic analysis revealed 46,XX.ish der(9)(3qter→3q28::9p21.1→9p22.3::9p22.3→9qter)(RP11-368G14+,RP11-299O8-,RP11-905L2++,RP11-775E6++). Her dysmorphic features are consistent with 3q29 microduplication syndrome and inv dup del(9p). Trio-based WES of the patient revealed no pathogenic single nucleotide variants causing epilepsy, but confirmed a 3q28q29 duplication involving FGF12, which encodes fibroblast growth factor 12. FGF12 positively regulates the activity of voltage-gated sodium channels. Recently, only one recurrent gain-of-function variant [NM_021032.4:c.341G>A:p.(Arg114His)] in FGF12 was found in a total of 10 patients with severe early-onset epilepsy. We propose that the patient's entire FGF12 duplication may be analogous to the gain-of-function variant in FGF12 in the epileptic phenotype of this patient.

13.
J Hum Genet ; 64(10): 967-978, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31337854

RESUMO

Cornelia de Lange syndrome (CdLS) is a rare multisystem disorder with specific dysmorphic features. Pathogenic genetic variants encoding cohesion complex subunits and interacting proteins (e.g., NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major causes of CdLS. However, there are many clinically diagnosed cases of CdLS without pathogenic variants in these genes. To identify further genetic causes of CdLS, we performed whole-exome sequencing in 57 CdLS families, systematically evaluating both single nucleotides variants (SNVs) and copy number variations (CNVs). We identified pathogenic genetic changes in 36 out of 57 (63.2 %) families, including 32 SNVs and four CNVs. Two known CdLS genes, NIPBL and SMC1A, were mutated in 23 and two cases, respectively. Among the remaining 32 individuals, four genes (ANKRD11, EP300, KMT2A, and SETD5) each harbored a pathogenic variant in a single individual. These variants are known to be involved in CdLS-like. Furthermore, pathogenic CNVs were detected in NIPBL, MED13L, and EHMT1, along with pathogenic SNVs in ZMYND11, MED13L, and PHIP. These three latter genes were involved in diseases other than CdLS and CdLS-like. Systematic clinical evaluation of all patients using a recently proposed clinical scoring system showed that ZMYND11, MED13L, and PHIP abnormality may cause CdLS or CdLS-like.

14.
Am J Hum Genet ; 105(2): 384-394, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31256876

RESUMO

Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.

15.
Am J Hum Genet ; 105(2): 403-412, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31303265

RESUMO

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

16.
Nat Genet ; 51(8): 1215-1221, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31332381

RESUMO

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult1-8, but skin biopsy enables its ante-mortem diagnosis9-12. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.

17.
J Hum Genet ; 64(9): 885-890, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270375

RESUMO

Pediatric hypertension can cause hypertensive emergencies, including hemorrhagic stroke, contributing to rare but serious childhood morbidity and mortality. Renovascular hypertension (RVH) is one of the major causes of secondary hypertension in children. Grange syndrome (MIM#602531) is a rare disease characterized by multiple stenosis or occlusion of the renal, abdominal, coronary, and cerebral arteries, which can cause phenotypes of RVH and fibromuscular dysplasia (MIM#135580). We report the case of a 7-year-old girl with Grange syndrome who showed RVH and multiple seizure episodes. At 1 year of age, she experienced seizures and sequential hemiparesis caused by a left thalamic hemorrhage without cerebral vascular anomalies. Chronic hypertension was observed, and abdominal computed tomography angiography showed characteristic bilateral renal artery stenosis. Whole-exome sequencing revealed a novel homozygous pathogenic variant in the YY1AP1 gene (NM_001198903.1: c.1169del: p.Lys390Argfs*12). Biallelic YY1AP1 mutations are known to cause Grange syndrome. Unlike previously reported patients, our patient presented with intracerebral hemorrhagic stroke without anomalous brain artery or bone fragility. The phenotype in our patient may help better understand this ultra-rare syndrome. Grange syndrome should be considered in patients presenting with childhood-onset hypertension and/or hemorrhagic stroke for early clinical intervention.

18.
Epilepsy Res ; 155: 106161, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31295639

RESUMO

Over the past decade there has been a substantial increase in genetic studies of brain malformations, fueled by the availability of improved technologies to study surgical tissue to address the hypothesis that focal lesions arise from focal, post-zygotic genetic disruptions. Traditional genetic studies of patients with malformations utilized leukocyte-derived DNA to search for germline variants, which are inherited or arise de novo in parental gametes. Recent studies have demonstrated somatic variants that arise post-zygotically also underlie brain malformations, and that somatic mutation explains a larger proportion of focal malformations than previously thought. We now know from studies of non-diseased individuals that somatic variation occurs routinely during cell division, including during early brain development when the rapid proliferation of neuronal precursor cells provides the ideal environment for somatic mutation to occur and somatic variants to accumulate. When confined to brain, pathogenic variants contribute to the "hidden genetics" of neurological diseases. With burgeoning novel high-throughput genetic technologies, somatic genetic variations are increasingly being recognized. Here we discuss accumulating evidence for the presence of somatic variants in normal brain tissue, review our current understanding of somatic variants in brain malformations associated with lesional epilepsy, and provide strategies to identify the potential contribution of somatic mutation to non-lesional epilepsies. We also discuss technologies that may improve detection of somatic variants in the future in these and other neurological conditions.

19.
Neurology ; 93(3): e237-e251, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31197031

RESUMO

OBJECTIVE: Intensive genetic analysis was performed to reveal comprehensive molecular insights into hypothalamic hamartoma (HH). METHODS: Thirty-eight individuals with HH were investigated by whole exome sequencing, target capture-based deep sequencing, or single nucleotide polymorphism (SNP) array using DNA extracted from blood leukocytes or HH samples. RESULTS: We identified a germline variant of KIAA0556, which encodes a ciliary protein, and 2 somatic variants of PTPN11, which forms part of the RAS/mitogen-activated protein kinase (MAPK) pathway, as well as variants in known genes associated with HH. An SNP array identified (among 3 patients) one germline copy-neutral loss of heterozygosity (cnLOH) at 6p22.3-p21.31 and 2 somatic cnLOH; one at 11q12.2-q25 that included DYNC2H1, which encodes a ciliary motor protein, and the other at 17p13.3-p11.2. A germline heterozygous variant and an identical somatic variant of DYNC2H1 arising from cnLOH at 11q12.2-q25 were confirmed in one patient (whose HH tissue, therefore, contains biallelic variants of DYNC2H1). Furthermore, a combination of a germline and a somatic DYNC2H1 variant was detected in another patient. CONCLUSIONS: Overall, our cohort identified germline/somatic alterations in 34% (13/38) of patients with HH. Disruption of the Shh signaling pathway associated with cilia or the RAS/MAPK pathway may lead to the development of HH.

20.
Nat Commun ; 10(1): 2884, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253780

RESUMO

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10-5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.


Assuntos
Ciliopatias/genética , Proteínas do Olho/genética , Predisposição Genética para Doença , Doenças Retinianas/genética , Elementos Alu/genética , Grupo com Ancestrais do Continente Asiático/genética , Genômica , Humanos , Japão , Mutação , Linhagem
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