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1.
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
2.
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
3.
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
4.
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
5.
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
6.
BMJ Case Rep ; 14(7)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253512

RESUMO

Neonatal Schwartz-Jampel syndrome type II is a rare and severe form of genetic disorder. Different from the classical appearance in infancy, neonatal presentation involves respiratory and feeding difficulties, along with characteristic pursed appearance of the mouth, myotonia, skeletal dysplasia and severe fatal hyperthermia. The clinical spectrum of this syndrome is so wide that it easily baffles with more common differentials. In this case report, a neonate born to third-degree consanguineous marriage with previous two abortions presented with respiratory difficulty, severe hyperthermia and feeding difficulty, which were daunting challenges to manage due to being refractory to standard line of management. Severe myotonia and gross dysmorphism were challenging dots to connect. Targeted exome sequencing was a ray of hope, which revealed homozygous mutation in the leukaemia inhibitory factor receptor gene on chromosome 5p13, confirming the genetic diagnosis for a fairly common spectrum of symptoms. The neonate later developed pneumoperitoneum and succumbed to underlying severe neonatal illness.


Assuntos
Osteocondrodisplasias , Consanguinidade , Face , Feminino , Humanos , Recém-Nascido , Hipertonia Muscular/diagnóstico , Hipertonia Muscular/genética , Mutação , Osteocondrodisplasias/complicações , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Gravidez
7.
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
8.
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
9.
BMC Musculoskelet Disord ; 22(1): 630, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34284742

RESUMO

BACKGROUND: Skeletal dysplasia is a heterogeneous group of disorders resulting from different genetic variants in humans. The current study was designed to identify the genetic causes of skeletal dysplasia and short stature in two consanguineous families from Pakistan, both comprised of multiple affected individuals. Patients in one family had proportionate short stature with reduced head circumference while affected individuals in the other family had disproportionate short stature. METHODS: Clinical data were obtained and radiological examinations of the index patients were completed. Whole genome sequencing for probands from both families were performed followed by Sanger sequencing to confirm segregation of identified variants in the respective families. In-silico pathogenicity score prediction for identified variant and amino acid conservation analysis was completed. RESULTS: Whole Genome Sequencing identified a known biallelic variant c.6176_6189delGTCAGCTGCCGAAG; p.(Gln2060ArgfsTer48) in PCNT gene and a novel biallelic variant c.174delC; p.(Asp60ThrfsTer7) in RAB33B gene respectively in affected members of the two families. Clinical imaging revealed platyspondyly and varus deformity in the legs of the affected members in the first family. Radiographs indicated severe platyspondyly, genu valgus deformity of legs and pectus carinatum for the patients in the second family. CONCLUSION: In this study we report the phenotypes and genetic variants in two unrelated families with two distinct forms of skeletal dysplasia. This study strengthens the previous findings that patients harboring PCNT variants are phenotypically homogeneous and also extends the genotypic spectrum of RAB33B variants.


Assuntos
Osteocondrodisplasias , Consanguinidade , Humanos , Paquistão , Linhagem , Fenótipo , Proteínas rab de Ligação ao GTP
10.
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
11.
BMC Pediatr ; 21(1): 282, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34134655

RESUMO

BACKGROUND: Hereditary cancer susceptibility syndrome (HCSS) contributes to the cancer predisposition at an early age, therefore, identification of HCSS has found to be crucial for surveillance, managing therapeutic interventions and refer the patients and their families for genetic counselling. The study aimed to identify ALL patients who meet the American College of Medical Genetics (ACMG) criteria and refer them for the genetic testing for HCSS as hereditary leukemia and hematologic malignancy syndrome, and to elucidate the significance of high consanguinity with the prevalence of inherited leukemia in Pakistani population. METHODS: A total of 300 acute lymphoblastic leukemia patients were recruited from the Children's Hospital, Lahore, Pakistan from December 2018 to September 2019. A structured self-reporting questionnaire based on family and medical history of the disease was utilized for the data collection. RESULTS: In our cohort, 60.40% of ALL patients were identified to meet ACMG criteria. Among them, a large number of patients (40.65%) solely fulfil the criteria due to the presence of parental consanguinity. However, parental consanguinity showed protective impact on the onset at early age of disease [OD = 0.44 (0.25-0.77), p-value = 0.00] while, a family history of cancer increased the risk of cardiotoxicity [OD = 2.46 (1.15-5.24), p-value = 0.02]. Parental consanguinity shows no significant impact on the family history of cancer and the number of relatives with cancer. CONCLUSIONS: More than 50% of the ALL patients were considered the strong candidates' for genetic testing of HCSS in the Pakistani population, and parental consanguinity was the leading criteria fulfilled by the individuals when assessed through ACMG guidelines. Our study suggests revisiting ACMG guidelines, especially for the criterion of parental consanguinity, and formulating the score based criteria based on; genetic research, the toxicology profile, physical features, personal and family history of cancer for the identification of patients for the genetic testing.


Assuntos
Predisposição Genética para Doença , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Consanguinidade , Humanos , Paquistão/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Síndrome , Estados Unidos
12.
Orphanet J Rare Dis ; 16(1): 278, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34130719

RESUMO

BACKGROUND: Consanguineous families have a relatively high prevalence of genetic disorders caused by bi-allelic mutations in recessive genes. This study aims to evaluate the effectiveness and efficiency of a consanguinity-based exome sequencing approach to capturing genetic mutations in inherited retinal dystrophy families with consanguineous marriages. METHODS: Ten unrelated consanguineous families with a proband affected by inherited retinal dystrophy were recruited in this study. All participants underwent comprehensive ophthalmic examinations. Whole exome sequencing was performed, followed by a homozygote-prior strategy to rapidly filter disease-causing mutations. Bioinformatic prediction of pathogenicity, Sanger sequencing and co-segregation analysis were carried out for further validation. RESULTS: In ten consanguineous families, a total of 10 homozygous mutations in 8 IRD genes were identified, including 2 novel mutations, c.1654_1655delAG (p. R552Afs*5) in gene FAM161A in a patient diagnosed with retinitis pigmentosa, and c.830T > C (p.L277P) in gene CEP78 in a patient diagnosed with cone and rod dystrophy. CONCLUSION: The genetic etiology in consanguineous families with IRD were successfully identified using consanguinity-based analysis of exome sequencing data, suggesting that this approach could provide complementary insights into genetic diagnoses in consanguineous families with variant genetic disorders.


Assuntos
Exoma , Distrofias Retinianas , Proteínas de Ciclo Celular , Consanguinidade , Análise Mutacional de DNA , Homozigoto , Humanos , Mutação , Linhagem , Distrofias Retinianas/genética , Sequenciamento Completo do Exoma
13.
J Pak Med Assoc ; 71(3): 816-821, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34057927

RESUMO

Objective: To explore the genetic cause of autosomal recessive retinitis pigmentosa in consanguineous families. METHODS: The multi-centre study was conducted from July 2015 to June 2018 at Liaquat University of Medical and Health Sciences, Jamshoro, the University of Sindh, Jamshoro, and Islamia University, Bahawalpur, Pakistan, and comprised families affected with non-syndromic autosomal recessive retinitis pigmentosa. Ophthalmological investigations were done to assess the fundus of the patients and the status of the disease. Pedigrees were drawn and family histories were recorded to find out the mode of inheritance. A 10cc sample of whole blood was obtained from each participant and deoxyribonucleic acid was extracted. Homozygosity mapping was performed using three short tandem repeat polymorphisms closely linked to phosphodiesterase 6A gene, and the linked families were Sanger-sequenced for identification of the mutation. Bioinformatic tools were used to design amplification refractory mutation system assay and to assess the protein structure and pathogenic effects of the mutation. RESULTS: In the 80 consanguineous families, there were 464 individuals, and, of them, 236(51%) were affected with their age ranging between 4 and 80 years. Family history and pedigree drawings revealed autosomal recessive retinitis pigmentosa with early childhood onset. Linkage analysis indicated the homozygosity in 6(7.5%) families. Sanger-sequencing revealed a common mutation c.304C>A (p.Arg102Ser); segregating with the disease in the linked families. Conclusion: The findings may offer effective genetic counselling and minimise disease penetration in consanguineous families.


Assuntos
Retinite Pigmentosa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Consanguinidade , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Proteínas do Olho/genética , Genes Recessivos , Humanos , Pessoa de Meia-Idade , Mutação , Paquistão , Retinite Pigmentosa/genética , Adulto Jovem
14.
Hum Genet ; 140(8): 1157-1168, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33959807

RESUMO

Infantile nystagmus syndrome (INS) denominates early-onset, involuntary oscillatory eye movements with different etiologies. Nystagmus is also one of the symptoms in oculocutaneus albinism (OCA), a heterogeneous disease mainly caused by defects in melanin synthesis or melanosome biogenesis. Dopachrome tautomerase (DCT, also called TYRP2) together with tyrosinase (TYR) and tyrosin-related protein 1 (TYRP1) is one of the key enzymes in melanin synthesis. Although DCT´s role in pigmentation has been proven in different species, until now only mutations in TYR and TYRP1 have been found in patients with OCA. Detailed ophthalmological and orthoptic investigations identified a consanguineous family with two individuals with isolated infantile nystagmus and one family member with subtle signs of albinism. By whole-exome sequencing and segregation analysis, we identified the missense mutation c.176G > T (p.Gly59Val) in DCT in a homozygous state in all three affected family members. We show that this mutation results in incomplete protein maturation and targeting in vitro compatible with a partial or total loss of function. Subsequent screening of a cohort of patients with OCA (n = 85) and INS (n = 25) revealed two heterozygous truncating mutations, namely c.876C > A (p.Tyr292*) and c.1407G > A (p.Trp469*), in an independent patient with OCA. Taken together, our data suggest that mutations in DCT can cause a phenotypic spectrum ranging from isolated infantile nystagmus to oculocutaneous albinism.


Assuntos
Albinismo Oculocutâneo/genética , Oxirredutases Intramoleculares/genética , Melaninas/biossíntese , Mutação de Sentido Incorreto , Nistagmo Congênito/genética , Adolescente , Albinismo Oculocutâneo/diagnóstico , Albinismo Oculocutâneo/enzimologia , Albinismo Oculocutâneo/patologia , Sequência de Bases , Calnexina/genética , Calnexina/metabolismo , Criança , Estudos de Coortes , Consanguinidade , Feminino , Regulação da Expressão Gênica , Células HEK293 , Homozigoto , Humanos , Oxirredutases Intramoleculares/deficiência , Masculino , Melaninas/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Monofenol Mono-Oxigenase/genética , Monofenol Mono-Oxigenase/metabolismo , Nistagmo Congênito/diagnóstico , Nistagmo Congênito/enzimologia , Nistagmo Congênito/patologia , Oxirredutases/genética , Oxirredutases/metabolismo , Linhagem , Sequenciamento Completo do Exoma , Adulto Jovem
17.
Theor Popul Biol ; 140: 32-43, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33901539

RESUMO

Consanguineous unions increase the frequency at which identical genomic segments are inherited along separate paths of descent, decreasing coalescence times for pairs of alleles drawn from an individual who is the offspring of a consanguineous pair. For an autosomal locus, it has recently been shown that the mean time to the most recent common ancestor (TMRCA) for two alleles in the same individual and the mean TMRCA for two alleles in two separate individuals both decrease with increasing consanguinity in a population. Here, we extend this analysis to the X chromosome, considering X-chromosomal coalescence times under a coalescent model with diploid, male-female mating pairs. We examine four possible first-cousin mating schemes that are equivalent in their effects on autosomes, but that have differing effects on the X chromosome: patrilateral-parallel, patrilateral-cross, matrilateral-parallel, and matrilateral-cross. In each mating model, we calculate mean TMRCA for X-chromosomal alleles sampled either within or between individuals. We describe a consanguinity effect on X-chromosomal TMRCA that differs from the autosomal pattern under matrilateral but not under patrilateral first-cousin mating. For matrilateral first cousins, the effect of consanguinity in reducing TMRCA is stronger on the X chromosome than on the autosomes, with an increased effect of parallel-cousin mating compared to cross-cousin mating. The theoretical computations support the utility of the model in understanding patterns of genomic sharing on the X chromosome.


Assuntos
Diploide , Família , Alelos , Consanguinidade , Feminino , Humanos , Masculino , Cromossomo X
18.
Genes (Basel) ; 12(3)2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807568

RESUMO

Gitelman syndrome (GS) and Bartter syndrome (BS) type III are both rare, recessively inherited salt-losing tubulopathies caused by SLC12A3 and CLCNKB mutations, respectively. We described a 48-year-old male patient with fatigue, carpopedal spasm, arthralgia, hypokalemic alkalosis, mild renal dysfunction, hypomagnesemia, hypocalciuria, hyperuricemia, normotension, hyperreninemia and chondrocalcinosis in knees and Achilles tendons. His parents are first cousin. Genetic analysis revealed simultaneous homozygous mutations in SLC12A3 gene with c.248G>A, p.Arg83Gln and CLCNKB gene with c.1171T>C, p.Trp391Arg. The second younger brother of the proband harbored the same simultaneous mutations in SLC12A3 and CLCNKB and exhibited similar clinical features except normomagnesemia and bilateral kidney stones. The first younger brother of the proband harbored the same homozygous mutations in CLCNKB and exhibited clinical features of hypokalemia, normomagnesemia, hypercalciuria and hyperuricemia. Potassium chloride, spironolactone and potassium magnesium aspartate were prescribed to the proband to correct electrolytic disturbances. Benzbromarone and febuxostat were prescribed to correct hyperuricemia. The dose of potassium magnesium aspartate was subsequently increased to alleviate arthralgia resulting from calcium pyrophosphate deposition disease (CPPD). To the best of our knowledge, we are the first to report an exceptionally rare case in an inbred Chinese pedigree with simultaneous homozygous mutations in SLC12A3 and CLCNKB. GS and BS type III have significant intrafamilial phenotype heterogeneity. When arthralgia is developed in patients with GS and BS, gout and CPPD should both be considered.


Assuntos
Síndrome de Bartter/genética , Canais de Cloreto/genética , Síndrome de Gitelman/genética , Adulto , Idoso , Substituição de Aminoácidos , Síndrome de Bartter/diagnóstico por imagem , China , Consanguinidade , Feminino , Síndrome de Gitelman/diagnóstico por imagem , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Membro 3 da Família 12 de Carreador de Soluto/genética
19.
Genes (Basel) ; 12(3)2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807935

RESUMO

BACKGROUND: Ichthyoses are a large group of hereditary cornification disorders, which are both clinically and etiologically heterogeneous and affect mostly all the skin surface of the patients. Ichthyosis has its origin in an ancient Greek word "ichthys" meaning fish, this is because the ichthyosis patients have dry, thickened, and scaly skin. There is an excess accumulation of epidermal cells resulting in the appearance of continuous and widespread scales on the body. There are many varieties of ichthyosis with a broad spectrum of intensity, severity, and associated symptoms, most of them are extremely rare. Ichthyosis vulgaris is the most frequently occurring type of ichthyoses. METHOD: The present study consists of four Pakistani ichthyosis families (A, B, C, and D). Whole exome sequencing (WES) approach was used to identify the pathogenic sequence variants in probands. The segregation of these variants in other participants was confirmed by Sanger sequencing. RESULTS: Total four variants including, two splice site (TGM1: c.2088 + 1G > A) and (SPINK5: c.882 + 1G > T), a missense (SULT2B1: c.419C > T; p. Ala140Val), and a nonsense (FLG: c.6109C > T; p. Arg2037Ter) variant were identified in families A, C, B, and D, respectively, as causative mutations responsible for ichthyosis in these families. CONCLUSION: Our study unravels the molecular etiology of the four Pakistani ichthyosis families and validates the involvement of TGM1, SULT2B1, SPINK5, and FLG, in the etiology of different forms of ichthyosis. In addition, this study also aims to give a detailed clinical report of the studied ichthyosis families.


Assuntos
Ictiose/genética , Mutação , Proteínas S100/genética , Inibidor de Serinopeptidase do Tipo Kazal 5/genética , Sulfotransferases/genética , Transglutaminases/genética , Adulto , Estudos de Casos e Controles , Criança , Consanguinidade , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Masculino , Paquistão , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
20.
Genes (Basel) ; 12(4)2021 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-33800529

RESUMO

Melanin pigment helps protect our body from broad wavelength solar radiation and skin cancer. Among other pigmentation disorders in humans, albinism is reported to manifest in both syndromic and nonsyndromic forms as well as with varying inheritance patterns. Oculocutaneous albinism (OCA), an autosomal recessive nonsyndromic form of albinism, presents as partial to complete loss of melanin in the skin, hair, and iris. OCA has been known to be caused by pathogenic variants in seven different genes, so far, according to all the currently published population studies. However, the detection rate of alleles causing OCA varies from 50% to 90%. One of the significant challenges of uncovering the pathological variant underlying disease etiology is inter- and intra-familial locus heterogeneity. This problem is especially pertinent in highly inbred populations. As examples of such familial locus heterogeneity, we present nine consanguineous Pakistani families with segregating OCA due to variants in one or two different known albinism-associated genes. All of the identified variants are predicted to be pathogenic, which was corroborated by several in silico algorithms and association with diverse clinical phenotypes. We report an individual affected with OCA carries heterozygous, likely pathogenic variants in TYR and OCA2, raising the question of a possible digenic inheritance. Altogether, our study highlights the significance of exome sequencing for the complete genetic diagnosis of inbred families and provides the ramifications of potential genetic interaction and digenic inheritance of variants in the TYR and OCA2 genes.


Assuntos
Albinismo Oculocutâneo/genética , Proteínas de Membrana Transportadoras/genética , Monofenol Mono-Oxigenase/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Consanguinidade , Feminino , Estudos de Associação Genética , Heterogeneidade Genética , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Proteínas de Membrana Transportadoras/química , Pessoa de Meia-Idade , Modelos Moleculares , Linhagem , Sequenciamento Completo do Exoma , Adulto Jovem
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