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1.
PLoS One ; 16(10): e0258777, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34669720

RESUMO

Erythrokeratodermia variabilis (EKV) is a rare disorder of cornification usually associated with dominant mutations in the GJB3 and GJB4 genes encoding connexins (Cx)31 and 30.3. Genetic heterogeneity of EKV has already been suggested. We investigated at the clinical and genetic level a consanguineous Tunisian family with 2 sisters presenting an autosomal recessive form of EKV to better characterize this disease. Mutational analysis initially screened the connexin genes and Whole-exome sequencing (WES) was performed to identify the molecular aetiology of the particular EKV phenotype in the proband. Migratory shaped erythematous areas are the initial presenting sign followed by relatively stable hyperkeratotic plaques are the two predominates characteristics in both patients. However, remarkable variability of morphological and dominating features of the disease were observed between patients. In particular, the younger sister (proband) exhibited ichthyosiform-like appearance suggesting Autosomal Recessive Congenital Ichthyosis (ARCI) condition. No causative mutations were detected in the GJB3 and GJB4 genes. WES results revealed a novel missense homozygous mutation in NIPAL4 gene (c.835C>G, p.Pro279Ala) in both patients. This variant is predicted to be likely pathogenic. In addition, in silico analysis of the mutated 3D domain structure predicted that this variant would result in NIPA4 protein destabilization and Mg2+ transport perturbation, pointing out the potential role of NIPAL4 gene in the development and maintenance of the barrier function of the epidermis. Taken togheter, these results expand the clinical phenotype associated with NIPAL4 mutation and reinforce our hypothesis of NIPAL4 as the main candidate gene for the EKV-like ARCI phenotype.


Assuntos
Eritroceratodermia Variável/genética , Mutação de Sentido Incorreto , Receptores de Superfície Celular/química , Receptores de Superfície Celular/genética , Sequenciamento Completo do Exoma/métodos , Criança , Conexinas/genética , Consanguinidade , Feminino , Humanos , Lactente , Simulação de Acoplamento Molecular , Linhagem , Fenótipo , Estabilidade Proteica , Tunísia
2.
PLoS One ; 16(10): e0258202, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34614013

RESUMO

Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM includes mental retardation, recurrent infections, hearing loss, dysmorphic features, and motor dysfunctions. AM has never been reported in Tunisia. We report here the clinical and genetic study of six patients from two Tunisian families with AM. The AM diagnosis was confirmed by an enzymatic activity assay. Genetic investigation was conducted by Sanger sequencing of the mutational hotspots for the first family and by ES analysis for the second one. In the first family, a frameshift duplication p.(Ser802GlnfsTer129) was identified in the MAN2B1 gene. For the second family, ES analysis led to the identification of a missense mutation p.(Arg229Trp) in the MAN2B1 gene in four affected family members. The p.(Ser802GlnfsTer129) mutation induces a premature termination codon which may trigger RNA degradation by the NMD system. The decrease in the levels of MAN2B1 synthesis could explain the severe phenotype observed in the index case. According to the literature, the p.(Arg229Trp) missense variant does not have an impact on MAN2B1 maturation and transportation, which correlates with a moderate clinical sub-type. To explain the intra-familial variability of cognitive impairment, exome analysis allowed the identification of two likely pathogenic variants in GHR and SLC19A3 genes potentially associated to cognitive decline. The present study raises awareness about underdiagnosis of AM in the region that deprives patients from accessing adequate care. Indeed, early diagnosis is critical in order to prevent disease progression and to propose enzyme replacement therapy.


Assuntos
Proteínas de Transporte/genética , Disfunção Cognitiva/genética , Consanguinidade , Predisposição Genética para Doença , Proteínas de Membrana Transportadoras/genética , alfa-Manosidose/genética , Audiometria , Sequência de Bases , Família , Feminino , Geografia , Humanos , Masculino , Mutação/genética , Linhagem , Fenótipo , Tunísia , Sequenciamento Completo do Exoma
3.
Eur J Endocrinol ; 185(6): 841-854, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34643546

RESUMO

Objective: CAV1 encodes caveolin-1, a major protein of plasma membrane microdomains called caveolae, involved in several signaling pathways. Caveolin-1 is also located at the adipocyte lipid droplet. Heterozygous pathogenic variants of CAV1 induce rare heterogeneous disorders including pulmonary arterial hypertension and neonatal progeroid syndrome. Only one patient was previously reported with a CAV1 homozygous pathogenic variant, associated with congenital generalized lipodystrophy (CGL3). We aimed to further delineate genetic transmission, clinical, metabolic, and cellular characteristics of CGL3. Design/Methods: In a large consanguineous kindred referred for CGL, we performed next-generation sequencing, as well as clinical, imagery, and metabolic investigations. We studied skin fibroblasts from the index case and the previously reported patient with CGL3. Results: Four patients, aged 8 months to 18 years, carried a new homozygous p.(His79Glnfs*3) CAV1 variant. They all displayed generalized lipodystrophy since infancy, insulin resistance, low HDL-cholesterol, and/or high triglycerides, but no pulmonary hypertension. Two patients also presented at the age of 15 and 18 years with dysphagia due to achalasia, and one patient had retinitis pigmentosa. Heterozygous parents and relatives (n = 9) were asymptomatic, without any metabolic abnormality. Patients' fibroblasts showed a complete loss of caveolae and no protein expression of caveolin-1 and its caveolin-2 and cavin-1 partners. Patients' fibroblasts also displayed insulin resistance, increased oxidative stress, and premature senescence. Conclusions: The CAV1 null variant investigated herein leads to an autosomal recessive congenital lipodystrophy syndrome. Loss of caveolin-1 and/or caveolae induces specific manifestations including achalasia which requires specific management. Overlapping phenotypic traits between the different CAV1-related diseases require further studies.


Assuntos
Caveolina 1/genética , Acalasia Esofágica/genética , Lipodistrofia Generalizada Congênita/genética , Adolescente , Cavéolas/patologia , Cavéolas/ultraestrutura , Caveolina 1/metabolismo , Caveolina 2/metabolismo , Senescência Celular , Criança , Pré-Escolar , Consanguinidade , Dislipidemias/metabolismo , Acalasia Esofágica/patologia , Feminino , Fibroblastos/patologia , Fibroblastos/ultraestrutura , Homozigoto , Humanos , Lactente , Lipodistrofia Generalizada Congênita/metabolismo , Lipodistrofia Generalizada Congênita/patologia , Masculino , Microscopia Eletrônica de Transmissão , Estresse Oxidativo , Linhagem , Proteínas de Ligação a RNA/metabolismo
4.
J Clin Invest ; 131(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623332

RESUMO

We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells. In naive CD4+ T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient's naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.


Assuntos
Genes rel , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/imunologia , Proteínas Proto-Oncogênicas c-rel/deficiência , Proteínas Proto-Oncogênicas c-rel/genética , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Criança , Consanguinidade , Feminino , Transplante de Células-Tronco Hematopoéticas , Homozigoto , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Ativação Linfocitária , Linfócitos/classificação , Linfócitos/imunologia , Mutação , Células Mieloides/imunologia , Doenças da Imunodeficiência Primária/terapia , Isoformas de Proteínas
5.
PLoS Genet ; 17(10): e1009848, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34662339

RESUMO

Patients with inherited retinal dystrophies (IRDs) were recruited from two understudied populations: Mexico and Pakistan as well as a third well-studied population of European Americans to define the genetic architecture of IRD by performing whole-genome sequencing (WGS). Whole-genome analysis was performed on 409 individuals from 108 unrelated pedigrees with IRDs. All patients underwent an ophthalmic evaluation to establish the retinal phenotype. Although the 108 pedigrees in this study had previously been examined for mutations in known IRD genes using a wide range of methodologies including targeted gene(s) or mutation(s) screening, linkage analysis and exome sequencing, the gene mutations responsible for IRD in these 108 pedigrees were not determined. WGS was performed on these pedigrees using Illumina X10 at a minimum of 30X depth. The sequence reads were mapped against hg19 followed by variant calling using GATK. The genome variants were annotated using SnpEff, PolyPhen2, and CADD score; the structural variants (SVs) were called using GenomeSTRiP and LUMPY. We identified potential causative sequence alterations in 61 pedigrees (57%), including 39 novel and 54 reported variants in IRD genes. For 57 of these pedigrees the observed genotype was consistent with the initial clinical diagnosis, the remaining 4 had the clinical diagnosis reclassified based on our findings. In seven pedigrees (12%) we observed atypical causal variants, i.e. unexpected genotype(s), including 4 pedigrees with causal variants in more than one IRD gene within all affected family members, one pedigree with intrafamilial genetic heterogeneity (different affected family members carrying causal variants in different IRD genes), one pedigree carrying a dominant causative variant present in pseudo-recessive form due to consanguinity and one pedigree with a de-novo variant in the affected family member. Combined atypical and large structural variants contributed to about 20% of cases. Among the novel mutations, 75% were detected in Mexican and 50% found in European American pedigrees and have not been reported in any other population while only 20% were detected in Pakistani pedigrees and were not previously reported. The remaining novel IRD causative variants were listed in gnomAD but were found to be very rare and population specific. Mutations in known IRD associated genes contributed to pathology in 63% Mexican, 60% Pakistani and 45% European American pedigrees analyzed. Overall, contribution of known IRD gene variants to disease pathology in these three populations was similar to that observed in other populations worldwide. This study revealed a spectrum of mutations contributing to IRD in three populations, identified a large proportion of novel potentially causative variants that are specific to the corresponding population or not reported in gnomAD and shed light on the genetic architecture of IRD in these diverse global populations.


Assuntos
Grupos Étnicos/genética , Degeneração Retiniana/genética , Consanguinidade , Análise Mutacional de DNA/métodos , Exoma/genética , Proteínas do Olho/genética , Feminino , Estudos de Associação Genética/métodos , Ligação Genética/genética , Genótipo , Humanos , Masculino , México , Mutação/genética , Paquistão , Linhagem , Retina/patologia , Sequenciamento Completo do Exoma/métodos , Sequenciamento Completo do Genoma/métodos
6.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638995

RESUMO

Hereditary congenital cataract (HCC) is clinically and genetically heterogeneous. We investigated HCC that segregates in three inbred families (LUCC03, LUCC16, and LUCC24). Ophthalmological examinations revealed cataracts with variability related to the age of onset segregating in a recessive manner in these families. Exome sequencing of probands identified a novel homozygous c.2710delG;p.(Val904Cysfs*36) EPHA2 variant in LUCC03 and a known homozygous c.2353G>A;p.(Ala785Thr) EPHA2 variant in the other two recessive families. EPHA2 encodes a transmembrane tyrosine kinase receptor, which is primarily involved in membrane-transport, cell-cell adhesion, and repulsion signaling processes. Computational structural modeling predicts that substitution of a threonine for an alanine p.(Ala785Thr) results in the formation of three new hydrogen bonds with the neighboring residues, which causes misfolding of EPHA2 in both scenarios. Insights from our study will facilitate counseling regarding the molecular and phenotypic landscape of EPHA2-related HCC.


Assuntos
Alelos , Catarata/congênito , Catarata/genética , Consanguinidade , Família , Mutação de Sentido Incorreto , Receptor EphA2/genética , Feminino , Homozigoto , Humanos , Masculino , Paquistão , Linhagem , Fenótipo , Sequenciamento Completo do Exoma/métodos
7.
East Mediterr Health J ; 27(8): 790-797, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34486715

RESUMO

Background: The worldwide incidence of congenital anomalies (CAs) is estimated at 3-7%, but actual numbers vary widely among countries. Birth defects are the most common causes of infantile mortality, accounting for ~25% of all neonatal deaths. Aims: To determine the prevalence of congenital anomalies in neonates in Fayoum Governorate; to classify malformations; and to clarify the association between congenital anomalies and possible risk factors. Methods: A cross-sectional study was conducted on 1000 infants in the neonatal intensive care unit and outpatient clinics of Fayoum University Hospital and Fayoum General Hospital during August 2017 to April 2018. Detailed history, clinical examination and relevant investigations were performed. Results: The prevalence of CAs was 7.4%. Major malformations accounted for 78.4% and minor malformations 21.6%. The most common CAs involved the cardiovascular system (32.4%), followed by musculoskeletal anomalies (18.9%), chromosomal anomalies (10.8%), anomalies of the central nervous system (9.5%), gastrointestinal tract (6.8%), genital system (5.4%), eyes, head and neck (5.4%), respiratory system (4.1%), multisystems (2 or more) (4.1%), and renal and urinary systems (2.7%). 82.4% of cases were from rural areas, 62.1% were male, 36.5% were female and 1.4% were ambiguous. 85.1% of neonates with malformations were full term. Conclusion: Cardiovascular, musculoskeletal and chromosomal anomalies were the most common CAs in our study. Positive consanguinity, poor attendance at antenatal clinics, rural residence and multiparty were the most common risk factors associated with CAs.


Assuntos
Anormalidades Congênitas , Anormalidades Congênitas/epidemiologia , Consanguinidade , Estudos Transversais , Egito/epidemiologia , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Gravidez , Prevalência , Fatores de Risco
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 833-837, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487524

RESUMO

OBJECTIVE: To analyze gene variants in a Chinese pedigree with oculocutaneous albinism (OCA). METHODS: Gene sequencing of the proband and his parents was performed using chip capture high-throughput sequencing and Sanger sequencing techniques, and PolyPhen-2, SIFT, MutationTaster, and FATHMM software were used to predict the function of new variants. At the same time,the pedigree and variant genes of 4 albinism patients from this pedigree were analyzed. RESULTS: Sequencing results showed that the proband's TYR gene (NM_000372) has c.230G>A (p.Arg77Gln) and c.120_121insG (p.Asp42GlyfsTer35) compound heterozygous variants. The proband's father carries c.230G>A heterozygous variant, and the mother carries c.120_121insG heterozygous variant, indicating that the proband's two variants are from his father and mother. The former is a known missense variant, which can cause abnormal or loss of the original function of the protein polypeptide chain. The latter c.120_121insG(p.Asp42GlyfsTer35) is an unreported frameshift variant of the TYR gene subregion (EX1; CDS1). PolyPhen-2, SIFT, MutationTaster and FATHMM predictions are all prompted as "harmful variants". This variant caused the amino acid encoded protein to terminate prematurely, producing a truncated protein, which eventually formed a 76-amino acid short-type TYR protein instead of the 529-amino acid wild-type TYR protein. Through the pedigree analysis, the four patients in the pedigree are all of the same type of compound heterozygous variants, and the disease-causing genes are all from the patient's parents. They belong to a special form of consanguineous marriage within 5 generations. CONCLUSION: The compound heterozygous variants of c.230G>A (p.Arg77Gln) and c.120_121insG (p.Asp42GlyfsTer35) of the TYR gene may underlie the disease in this pedigree. The gene sequencing results enrich the variant spectrum of the TYR gene, and has facilitated molecular diagnosis for the patient.


Assuntos
Albinismo Oculocutâneo , Albinismo Oculocutâneo/genética , Consanguinidade , Heterozigoto , Humanos , Mutação , Linhagem
9.
J Pak Med Assoc ; 71(9): 2250-2254, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34580524

RESUMO

Psychological disturbance (PD) or cerebral dysfunction (CD) covers several clinical areas, and has defining features of mental retardation. Recently, we conducted a study to investigate heritable heterogeneity in Pakistani consanguineous couples with recessive autosomal intellectual abnormalities. A cohort of three consanguineous families with multiple birth defects, belonging two to district lower Dir and one to district Lodhra, were selected for molecular analysis. All the affected individuals in the cohort showed autosomal recessive non-syndromic mental disturbances. DNA was extracted and subjected to Single tagged sequence (STS) marker analyses to all known non-syndromic autosomal recessive mental retardation (NS-ARMR) genes, while autozygosity mapping was performed by advanced SNP techniques. Fragment analyses of the NS-ARMR disease genes CRBN, CC2D2A, PRSS12, GRIK2, TUSC3, and CC2D1A using polymorphic STS markers confirmed these to be contender genes for the alteration. Mapping of autozygosity in all the study subjects using genome study revealed nine novel linkage intervals, i.e. four intervals for MR4, two intervals for MR8 and three intervals for MR13. In spite of being a monogenic condition, autosomal recessive mental retardation shows genetic heterogeneity and several genes are involved in different families; hence, there is a chance for involvement of separate gene in each family.


Assuntos
Deficiência Intelectual , Proteínas Adaptadoras de Transdução de Sinal , Consanguinidade , Genes Recessivos , Heterogeneidade Genética , Humanos , Deficiência Intelectual/genética , Paquistão , Linhagem , Ubiquitina-Proteína Ligases
10.
Hum Genet ; 140(12): 1679-1693, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34545459

RESUMO

The highly conserved YrdC domain-containing protein (YRDC) interacts with the well-described KEOPS complex, regulating specific tRNA modifications to ensure accurate protein synthesis. Previous studies have linked the KEOPS complex to a role in promoting telomere maintenance and controlling genome integrity. Here, we report on a newborn with a severe neonatal progeroid phenotype including generalized loss of subcutaneous fat, microcephaly, growth retardation, wrinkled skin, renal failure, and premature death at the age of 12 days. By trio whole-exome sequencing, we identified a novel homozygous missense mutation, c.662T > C, in YRDC affecting an evolutionary highly conserved amino acid (p.Ile221Thr). Functional characterization of patient-derived dermal fibroblasts revealed that this mutation impairs YRDC function and consequently results in reduced t6A modifications of tRNAs. Furthermore, we established and performed a novel and highly sensitive 3-D Q-FISH analysis based on single-telomere detection to investigate the impact of YRDC on telomere maintenance. This analysis revealed significant telomere shortening in YRDC-mutant cells. Moreover, single-cell RNA sequencing analysis of YRDC-mutant fibroblasts revealed significant transcriptome-wide changes in gene expression, specifically enriched for genes associated with processes involved in DNA repair. We next examined the DNA damage response of patient's dermal fibroblasts and detected an increased susceptibility to genotoxic agents and a global DNA double-strand break repair defect. Thus, our data suggest that YRDC may affect the maintenance of genomic stability. Together, our findings indicate that biallelic variants in YRDC result in a developmental disorder with progeroid features and might be linked to increased genomic instability and telomere shortening.


Assuntos
Deficiências do Desenvolvimento/genética , Proteínas de Ligação ao GTP/genética , Progéria/genética , Proteínas de Ligação a RNA/genética , Alelos , Consanguinidade , Dano ao DNA , Deficiências do Desenvolvimento/patologia , Genoma Humano , Instabilidade Genômica , Homozigoto , Humanos , Recém-Nascido , Masculino , Mutação , Linhagem , Progéria/patologia , RNA de Transferência/genética , Análise de Sequência de RNA , Encurtamento do Telômero
11.
PLoS One ; 16(9): e0256603, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34473761

RESUMO

From administrative registers of last names in Santiago, Chile, we create a surname affinity network that encodes socioeconomic data. This network is a multi-relational graph with nodes representing surnames and edges representing the prevalence of interactions between surnames by socioeconomic decile. We model the prediction of links as a knowledge base completion problem, and find that sharing neighbors is highly predictive of the formation of new links. Importantly, We distinguish between grounded neighbors and neighbors in the embedding space, and find that the latter is more predictive of tie formation. The paper discusses the implications of this finding in explaining the high levels of elite endogamy in Santiago.


Assuntos
Mineração de Dados/estatística & dados numéricos , Aprendizado de Máquina , Nomes , Linhagem , Chile , Consanguinidade , Feminino , Humanos , Masculino , Classe Social
12.
Braz J Biol ; 83: e246040, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34378666

RESUMO

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a congenitally reduced head circumference (-3 to -5 SD) and non-progressive intellectual disability. The objective of the study was to evaluate pathogenic mutations in the ASPM gene to understand etiology and molecular mechanism of primary microcephaly. Blood samples were collected from various families across different remote areas of Pakistan from February 2017 to May 2019 who were identified to be affected with primary microcephaly. DNA extraction was performed using the salting-out method; the quality and quantity of DNA were evaluated using spectrophotometry and 1% agarose gel electrophoresis, respectively in University of the Punjab. Mutation analysis was performed by whole exome sequencing from the Cologne Center for Genomics, University of Cologne. Sanger sequencing was done in University of the Punjab to confirm the pathogenic nature of mutation. A novel 4-bp deletion mutation c.3877_3880delGAGA was detected in exon 17 of the ASPM gene in two primary microcephaly affected families (A and B), which resulted in a frame shift mutation in the gene followed by truncated protein synthesis (p.Glu1293Lysfs*10), as well as the loss of the calmodulin-binding IQ domain and the Armadillo-like domain in the ASPM protein. Using the in-silico tools Mutation Taster, PROVEAN, and PolyPhen, the pathogenic effect of this novel mutation was tested; it was predicted to be "disease causing," with high pathogenicity scores. One previously reported mutation in exon 24 (c.9730C>T) of the ASPM gene resulting in protein truncation (p.Arg3244*) was also observed in family C. Mutations in the ASPM gene are the most common cause of MCPH in most cases. Therefore, enrolling additional affected families from remote areas of Pakistan would help in identifying or mapping novel mutations in the ASPM gene of primary microcephaly.


Assuntos
Microcefalia , Proteínas do Tecido Nervoso , Consanguinidade , Humanos , Microcefalia/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Paquistão
13.
F1000Res ; 10: 207, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34354814

RESUMO

Background: Whole exome sequencing (WES) is becoming part of routine clinical and diagnostic practice. In the investigation of inherited cystic kidney disease and renal ciliopathy syndromes, WES has been extensively applied in research studies as well as for diagnostic utility to detect various novel genes and variants. The yield of WES critically depends on the characteristics of the patient population. Methods: In this study, we selected 8 unrelated Omani children, presenting with renal ciliopathy syndromes with a positive family history and originating from consanguineous families. We performed WES in affected children to determine the genetic cause of disease and to test the yield of this approach, coupled with homozygosity mapping, in this highly selected population. DNA library construction and WES was carried out using SureSelect Human All Exon V6 Enrichment Kit and Illumina HiSeq platform. For variants filtering and annotation Qiagen Variant Ingenuity tool was used. Nexus copy number software from BioDiscovery was used for evaluation of copy number variants and whole gene deletions. Patient and parental DNA was used to confirm mutations and the segregation of alleles using Sanger sequencing. Results: Genetic analysis identified 4 potential causative homozygous variants each confirmed by Sanger sequencing in 4 clinically relevant ciliopathy syndrome genes, ( TMEM231, TMEM138, WDR19 and BBS9), leading to an overall diagnostic yield of 50%. Conclusions: WES coupled with homozygosity mapping provided a diagnostic yield of 50% in this selected population. This genetic approach needs to be embedded into clinical practise to allow confirmation of clinical diagnosis, to inform genetic screening as well as family planning decisions. Half of the patients remain without diagnosis highlighting the technical and interpretational hurdles that need to be overcome in the future.


Assuntos
Ciliopatias , Exoma , Criança , Ciliopatias/diagnóstico , Ciliopatias/genética , Consanguinidade , Exoma/genética , Humanos , Síndrome , Sequenciamento Completo do Exoma
14.
Asian J Psychiatr ; 64: 102814, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34425412

RESUMO

BACKGROUND: Studies from certain regions of the world indicate that consanguineous marriages are a risk factor for the development of schizophrenia in offspring. However the evidence is inconsistent partly due to methodological limitation of which hospital based recruitment contributing to significant bias. The studies from the Indian subcontinent, is scarce, where rates of consanguinity is high. METHODS: The schizophrenia patients living in a geographically defined rural south Indian community and randomly selected controls dwelling in the same community sharing sociocultural, economic and lifestyle factors were recruited. They were assessed for parental consanguinity using the clinical interviews as well as DNA-based estimates. The latter was conducted by calculating the coefficient of inbreeding 'f'. A participant was considered to have consanguineous parentage if his/her parents shared a common ancestor no more remote than a great-great-grandparent, corresponding to DNA-based estimates of 'f' ≥ 0.0156. RESULTS: The rates of parental consanguinity assessed by clinical interview were comparable in both groups (Cases: 10.71 %, Controls: 7.25 %; χ2 = 0.493, p = 0.4825). However, DNA-based rates of parental consanguinity showed that 'f' was significantly higher among cases than controls (Mann-Whitney U = 11315.5; p = 0.022). Seventy-five cases (62.5 %) and 108 control participants (48.6 %) had 'f' ≥ 0.0156 (χ2 = 6.008; p = 0.014). The results were consistent across different quality control measures. CONCLUSION: Schizophrenia is associated with higher parental consanguinity, suggesting a role for multiple recessive risk alleles in its etiology. Replication in future studies in diverse settings would add further strength to this.


Assuntos
População Rural , Esquizofrenia , Consanguinidade , Feminino , Humanos , Índia/epidemiologia , Masculino , Pais , Esquizofrenia/epidemiologia , Esquizofrenia/genética
15.
Hum Reprod ; 36(10): 2793-2804, 2021 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-34392356

RESUMO

STUDY QUESTION: Can whole-exome sequencing (WES) reveal pathogenic mutations in two consanguineous Pakistani families with infertile patients? SUMMARY ANSWER: A homozygous spermatogenesis associated 22 (SPATA22) frameshift mutation (c.203del), which disrupts the interaction with meiosis specific with OB-fold (MEIOB), and a MEIOB splicing mutation (c.683-1G>A) that led to loss of MEIOB protein cause familial infertility. WHAT IS KNOWN ALREADY: MEIOB and SPATA22, direct binding partners and functional collaborators, form a meiosis-specific heterodimer that regulates meiotic recombination. The protein stability and the axial localization of MEIOB and SPATA22 depend on each other. Meiob and Spata22 knockout mice have the same phenotypes: mutant spermatocytes can initiate meiotic recombination but are unable to complete DSB repair, leading to crossover formation failure, meiotic prophase arrest, and sterility. STUDY DESIGN, SIZE, DURATION: We performed WES for the patients and controls in two consanguineous Pakistani families to screen for mutations. The pathogenicity of the identified mutations was assessed by in vitro assay and mutant mouse model. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two consanguineous Pakistani families with four patients (three men and one woman) suffering from primary infertility were recruited. SPATA22 and MEIOB mutations were screened from the WES data, followed by functional verification in cultured cells and mice. MAIN RESULTS AND THE ROLE OF CHANCE: A homozygous SPATA22 frameshift mutation (c.203del) was identified in a patient with non-obstructive azoospermia (NOA) from a consanguineous Pakistani family and a homozygous MEIOB splicing mutation (c.683-1G>A) was identified in two patients with NOA and one infertile woman from another consanguineous Pakistani family. The SPATA22 mutation destroyed the interaction with MEIOB. The MEIOB splicing mutation induced Exon 9 skipping, which causes a 32aa deletion in the oligonucleotide-binding domain without affecting the interaction between MEIOB and SPATA22. Furthermore, analyses of the Meiob mutant mice modelling the patients' mutation revealed that the MEIOB splicing mutation leads to loss of MEIOB proteins, abolished SPATA22 recruitment on chromosome axes, and meiotic arrest due to meiotic recombination failure. Thus, our study suggests that SPATA22 and MEIOB may both be causative genes for human infertility. LIMITATIONS, REASONS FOR CAUTION: As SPATA22 and MEIOB are interdependent and essential for meiotic recombination, screening for mutations of SPATA22 and MEIOB in both infertile men and women in larger cohorts is important to further reveal the role of the SPATA22 and MEIOB heterodimer in human fertility. WIDER IMPLICATIONS OF THE FINDINGS: These findings provide direct clinical and functional evidence that mutations in SPATA22 and MEIOB can cause meiotic recombination failure, supporting a role for these mutations in human infertility and their potential use as targets for genetic diagnosis of human infertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Key Research and Developmental Program of China (2018YFC1003900, 2018YFC1003700, and 2019YFA0802600), the National Natural Science Foundation of China (31890780, 31630050, 32061143006, 82071709, and 31871514), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19000000). The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.


Assuntos
Azoospermia , Infertilidade/genética , Meiose , Animais , Proteínas de Ciclo Celular/genética , Consanguinidade , Proteínas de Ligação a DNA/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Mutação , Espermatogênese , Sequenciamento Completo do Exoma
16.
Exp Eye Res ; 211: 108714, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34390733

RESUMO

Mutations in Retinitis pigmentosa GTPase regulator gene (RPGR) are the most common cause of X-linked retinitis pigmentosa (RP). Almost 60% of disease-causing RPGR mutations are located in ORF-15 region which cannot be detected by Next Generation Sequencing (NGS) due to the existence of highly repetitive regions. An Iranian family with a priori diagnosis of autosomal dominant RP was studied by Sanger sequencing of ORF15 of RPGR gene after an inconclusive NGS result. A frameshift two-base-pair deletion (c.2323_2324del, p.Arg775Glufs*59) in this region was segregating in both affected hemizygous males and affected homozygous females. To our knowledge, this is the first example of homozygous females for RPGR-ORF15 mutations.


Assuntos
Proteínas do Olho/genética , Genes Ligados ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação/genética , Fases de Leitura Aberta/genética , Retinite Pigmentosa/genética , Grupo com Ancestrais do Continente Asiático/genética , Criança , Consanguinidade , Análise Mutacional de DNA , Éxons/genética , Feminino , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Linhagem , Retinite Pigmentosa/epidemiologia
17.
Hastings Cent Rep ; 51(5): 8-11, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34351628

RESUMO

This case study about an infant with epidermolysis bullosa and his fourteen-year-old mother involves pediatric genomic testing and concerns about the adolescent parent's decision-making capacity. Four commentaries explore ethics issues in the case, including the following challenges: The current ethics guidelines regarding informed decision-making for genomic testing and return of results have been relatively silent on how to involve parents who are minors in decision-making on behalf of their children. This lack of guidance can be particularly difficult for physicians when genetic test results revealing consanguinity raise concerns about sexual abuse of a minor, provoking questions about mandatory reporting requirements. Finally, medical teams may find themselves having to evaluate an adolescent parent's capacity in making medical decisions for her child while questioning the role and relationship of her support person.


Assuntos
Mães , Pais , Adolescente , Criança , Consanguinidade , Tomada de Decisões , Feminino , Testes Genéticos , Humanos , Lactente , Consentimento Livre e Esclarecido
18.
Orphanet J Rare Dis ; 16(1): 317, 2021 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-34273994

RESUMO

BACKGROUND: Developmental and epileptic encephalopathies (DEE) are chronic neurological conditions where epileptic activity contributes to the progressive disruption of brain function, frequently leading to impaired motor, cognitive and sensory development. PATIENTS AND METHODS: The present study reports a clinical investigation and a molecular analysis by Next Generation Sequencing (NGS) of a large consanguineous family comprising several cases of developmental and epileptic encephalopathy. Bioinformatic prediction and molecular docking analysis were also carried out. RESULTS: The majority of patients in our studied family had severe developmental impairments, early-onset seizures, brain malformations such as cortical atrophy and microcephaly, developmental delays and intellectual disabilities. The molecular investigations revealed a novel homozygous variant c.1411G>A (p.Gly471Arg) in the GRM7 gene which was segregating with the disease in the family. Bioinformatic tools predicted its pathogenicity and docking analysis revealed its potential effects on mGlu7 protein binding to its ligand. CONCLUSION: Our results contribute to a better understanding of the impact of GRM7 variants for the newly described associated phenotype.


Assuntos
Epilepsia , Consanguinidade , Epilepsia/genética , Humanos , Ligantes , Simulação de Acoplamento Molecular , Mutação , Receptores de Glutamato Metabotrópico
19.
J Stroke Cerebrovasc Dis ; 30(9): 105997, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34303089

RESUMO

OBJECTIVES: To identify the underlying genetic defect for a consanguineous family with an unusually high number of members affected by cerebral small vessel disease. MATERIALS AND METHODS: A total of 6 individuals, of whom 3 are severely affected, from the family were clinically and radiologically evaluated. SNP genotyping was performed in multiple members to demonstrate genome-wide runs-of-homozygosity. Coding variants in the most likely candidate gene, HTRA1 were explored by Sanger sequencing. Published HTRA1-related phenotypes were extensively reviewed to explore the effect of number of affected alleles on phenotypic expression. RESULTS: Genome-wide homozygosity mapping identified a 3.2 Mbp stretch on chromosome 10q26.3 where HTRA1 gene is located. HTRA1 sequencing revealed an evolutionarily conserved novel homozygous c.824C>T (p.Pro275Leu) mutation, affecting the serine protease domain of HtrA1. Early-onset of cognitive and motor deterioration in homozygotes are in consensus with CARASIL. However, there was a clear phenotypic variability between homozygotes which includes alopecia, a suggested hallmark of CARASIL. All heterozygotes, presenting as CADASIL type 2, had spinal disk degeneration and several neuroimaging findings, including leukoencephalopathy and microhemorrhage despite a lack of severe clinical presentation. CONCLUSION: Here, we clearly demonstrate that CARASIL and CADASIL type 2 are two clinical consequences of the same disorder with different severities thorough the evaluation of the largest collection of homozygotes and heterozygotes segregating in a family. Considering the semi-dominant inheritance of HTRA1-related phenotypes, genetic testing and clinical follow-up must be offered for all members of a family with HTRA1 mutations regardless of symptoms.


Assuntos
Alopecia/genética , CADASIL/genética , Infarto Cerebral/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Leucoencefalopatias/genética , Mutação , Doenças da Coluna Vertebral/genética , Adulto , Idade de Início , Alopecia/diagnóstico , Alopecia/fisiopatologia , CADASIL/diagnóstico , CADASIL/fisiopatologia , Infarto Cerebral/diagnóstico , Infarto Cerebral/fisiopatologia , Consanguinidade , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Homozigoto , Humanos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Índice de Gravidade de Doença , Doenças da Coluna Vertebral/diagnóstico , Doenças da Coluna Vertebral/fisiopatologia
20.
Cytogenet Genome Res ; 161(3-4): 153-159, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34229322

RESUMO

Terminal deletions in the long arm of chromosome 4 are an uncommon event, with a worldwide incidence of approximately 0.001%. The majority of these deletions occur de novo. Terminal deletion cases are usually accompanied by clinical findings that include facial and cardiac anomalies, as well as intellectual disability. In this study, we describe the case of a 2-year-old girl, the fourth child born to consanguineous parents. While her karyotype was normal, a homozygous deletion was identified in the chromosome 4q35.2 region by subtelomeric FISH. A heterozygous deletion of the chromosome 4q35.2 region was observed in both parents. According to the literature, this is the first report of a case that has inherited a homozygous deletion of chromosome 4qter from carrier parents. Subsequent array-CGH analyses were performed on both the case and her parents. Whole-exome sequencing was also carried out to determine potential variants. We detected a NM_001111125.3:c.2329G>T (p.Glu777Ter) nonsense variant of the IQSEC2 gene in the girl, a variant that is related to X-linked intellectual disability.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 4/genética , Códon sem Sentido , Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Pré-Escolar , Consanguinidade , Feminino , Genes Ligados ao Cromossomo X/genética , Homozigoto , Humanos , Cariotipagem , Telômero/genética , Sequenciamento Completo do Exoma
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