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1.
Hum Genet ; 138(10): 1123-1142, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31312899

RESUMO

The study of runs of homozygosity (ROH) can shed light on population demographic history and cultural practices. We present a fine-scale ROH analysis of 1679 individuals from 28 sub-Saharan African (SSA) populations along with 1384 individuals from 17 worldwide populations. Using high-density SNP coverage, we could accurately identify ROH > 300 kb using PLINK software. The genomic distribution of ROH was analysed through the identification of ROH islands and regions of heterozygosity (RHZ). The analyses showed a heterogeneous distribution of autozygosity across SSA, revealing complex demographic histories. They highlight differences between African groups and can differentiate the impact of consanguineous practices (e.g. among the Somali) from endogamy (e.g. among several Khoe and San groups). Homozygosity cold and hotspots were shown to harbour multiple protein coding genes. Studying ROH therefore not only sheds light on population history, but can also be used to study genetic variation related to adaptation and potentially to the health of extant populations.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Genética Populacional , Homozigoto , África ao Sul do Saara , Consanguinidade , Cruzamentos Genéticos , Análise de Dados , Demografia , Variação Genética , Genômica/métodos , Geografia , Humanos
2.
Gene ; 708: 10-13, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31078656

RESUMO

Autosomal recessive cerebellar ataxia is heterogeneous inherited neurodegenerative disorders with more than 70 involved genes. The development of next generation sequencing opens a new window in rapid diagnosis of such heterogeneous condition in medical genetics laboratories. Here, we present ADCK3; del.CD (229-230) mutation in an Iranian consanguineous family with three cerebellar ataxic boys using whole exome sequencing. The mutation was predicted pathogenic and all the affected individuals were homozygous for the variant. Although, the ADCK3 was previously reported as one of the master genes of ARSC, our mutation was novel as has been not previously reported in dbSNP or literature.


Assuntos
Proteínas Mitocondriais/genética , Ataxias Espinocerebelares/genética , Consanguinidade , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Irã (Geográfico) , Masculino , Linhagem , Deleção de Sequência , Sequenciamento Completo do Exoma
3.
J Ayub Med Coll Abbottabad ; 31(2): 290-292, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31094135

RESUMO

Yunis-Varon syndrome is a rare autosomal recessive disorder with characteristic facial features and limb anomalies. We report a neonate born to consanguineously married normal parents with typical clinical and radiologic features of Yunis-Varon syndrome along with complete cleft lip and palate: an infrequent association. The family had two previous babies with similar features who died in infancy. This is a first reported case of Yunis-Varon syndrome in Pakistan.


Assuntos
Displasia Cleidocraniana , Displasia Ectodérmica , Deformidades Congênitas dos Membros , Micrognatismo , Fenda Labial , Fissura Palatina , Consanguinidade , Evolução Fatal , Feminino , Humanos , Recém-Nascido , Paquistão
4.
Medicine (Baltimore) ; 98(22): e15928, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31145360

RESUMO

Congenital chloride losing diarrhea (CCLD) is a rare type of chronic watery diarrhea due to mutations in SLC26A3 gene leading to defective chloride-bicarbonate exchanges with the resultant loss of chloride and retention of bicarbonate.We aim to define pediatric Saudi CCLD patients' characteristics to achieve prompt diagnosis, management, follow up with good quality of life, and prevention of complications in these patients.We carried retrospective data review of demographic, clinical, laboratory, radiographic, and outcome of all pediatric patients fulfilling the criteria of CCLD over 10 years from 2004 to 2014 from a single center in Taif region, Saudi Arabia.Forty-nine patients fulfilled the criteria of CCLD from 21 families with more than one affected patient in the same family in 90% of them and positive consanguinity in 91% of the cohort. Most patients were born preterm with intrauterine growth restriction and usually neonatal intensive care unit (NICU) admissions with prematurity and its complications. Thirteen patients were discharged without diagnosis of CCLD and 3 were misdiagnosed as intestinal obstruction with unnecessary surgical intervention. Many complications do existed with renal complications being the most common with three patients received renal transplantation.Prematurity with abdominal distension and stool like urine were the commonest presentation of CCLD in Saudi children. Positive consanguinity and more than one affected sibling are present in most of our cohort.High index of suspicion by clinicians is a cornerstone for early diagnosis with subsequent favorable outcome.A multicenter national incidence study of CCLD in KSA and its genetic attributes is recommended. Premarital screening should be implemented specially for consanguineous marriage.


Assuntos
Diarreia/congênito , Doenças do Prematuro/epidemiologia , Erros Inatos do Metabolismo/epidemiologia , Consanguinidade , Diarreia/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Unidades de Terapia Intensiva Neonatal , Masculino , Estudos Retrospectivos , Arábia Saudita/epidemiologia
5.
BMC Med Genet ; 20(1): 73, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060517

RESUMO

BACKGROUND: Pathogenic variants associated with hereditary breast cancer have been reported for BRCA1 and BRCA2 (BRCA1/2) genes in patients from multiple ethnicities, but limited information is available from sub-Saharan African populations. We report a BRCA2 pathogenic variant in a Senegalese family with hereditary breast cancer. METHODS: An index case from a consanguineous family and nineteen healthy female relatives were recruited after informed consent. Along with this family, 14 other index cases with family history of breast cancer were also recruited. For the control populations we recruited 48 healthy women with no cancer diagnosis and 48 women diagnosed with sporadic breast cancer without family history. Genomic DNA was extracted from peripheral blood. All BRCA2 exons were amplified by PCR and sequenced. Sequences were compared to the BRCA2 GenBank reference sequence (NM_000059.3) using Alamut Software. RESULTS: We identified a novel nonsense pathogenic variant c.5219 T > G; p.(Leu1740Ter) in exon 11 of BRCA2 in the index case. The pathogenic variant was also identified in three sisters and one daughter, but was absent in the controls and unrelated cases. CONCLUSIONS: This is the first report of a novel BRCA2 pathogenic variant in a Senegalese family with hereditary breast cancer. This result confirms the diversity of hereditary breast cancer pathogenic variants across populations and extends our knowledge of genetic susceptibility to breast cancer in Africa.


Assuntos
Neoplasias da Mama/patologia , Consanguinidade , Genes BRCA2 , Predisposição Genética para Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Senegal , Análise de Sobrevida
6.
Gene ; 706: 1-5, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31009684

RESUMO

BACKGROUND: Mucopolysaccharidosis (MPS) type VI, also known as Maroteaux-Lamy syndrome, is an autosomal recessive lysosomal storage disorder caused by a deficiency in arylsulfatase B (ARSB) enzyme. Our objectives were to investigate clinical phenotypes and performed molecular studies in Iranian patients with MPS VI, for the first time, in the southwestern Iran. METHODS: We studied 14 cases from 10 unrelated kindreds with MPS VI that were enrolled during 8 years. The mutational analysis of coding and flanking regions of ARSB gene was performed for the patients and their families using genomic DNA from whole blood by direct sequencing. RESULTS: All cases had parental consanguinity. Except one who had Fars ethnicity and presented with a very mild degree of coarse face, but normal otherwise, even near normal height, all were from Arab ethnicity with characteristic phenotypes including severe facial changes, cardiac involvement and dysostosis multiplex. Sequencing analysis of ARSB gene revealed four pathogenic homozygote mutations, including a novel nonsense mutation c.281C>A (p.Ser94X) in 9 patients, as well as, a known nonsense mutation c.753C>G (p.Try251X) in 3 cases, and two missense mutations c.904G>A (p.Gly302Arg) and c.454C>T (p.Arg152Trp) in two cases. The type of mutations affected the severity patient's phenotypes. CONCLUSIONS: These findings increased the genetic databases of Iranian patients with MPS VI and would be so much helpful for the high-risk families to speed the detection of carriers with accuracy and perform the prenatal test of disorder with cost-effective in this population.


Assuntos
Mucopolissacaridose VI/genética , N-Acetilgalactosamina-4-Sulfatase/genética , Adulto , Consanguinidade , DNA/genética , Análise Mutacional de DNA/métodos , Éxons , Feminino , Humanos , Irã (Geográfico) , Masculino , Mucopolissacaridose VI/enzimologia , Mucopolissacaridose VI/metabolismo , Mutação/genética , N-Acetilgalactosamina-4-Sulfatase/metabolismo , N-Acetilgalactosamina-4-Sulfatase/fisiologia , Fenótipo , Análise de Sequência de DNA/métodos
7.
Cytogenet Genome Res ; 157(4): 189-196, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30974434

RESUMO

Hypohidrotic or anhidrotic ectodermal dysplasia (HED/EDA) is characterized by impaired development of the hair, teeth, or sweat glands. HED/EDA is inherited in an X-linked, autosomal dominant, or autosomal recessive pattern and caused by the pathogenic variants in 4 genes: EDA, EDAR, EDARADD, and WNT10A. The aim of the present study was to perform molecular screening of these 4 genes in a cohort of Turkish individuals diagnosed with HED/EDA. We screened for pathogenic variants of WNT10A, EDA, EDAR, and EDARADD through Sanger sequencing. We further assessed the clinical profiles of the affected individuals in order to establish phenotype-genotype correlation. In 17 (63%) out of 27 families, 17 pathogenic variants, 8 being novel, were detected in the 4 well-known ectodermal dysplasia genes. EDAR and EDA variants were identified in 6 families each, WNT10A variants in 4, and an EDARADD variant in 1, accounting for 35.3, 35.3, 23.5, and 5.9% of mutation-positive families, respectively. The low mutation detection rate of the cohort and the number of the EDAR pathogenic variants being as high as the EDA ones were the most noteworthy findings which could be attributed to the high consanguinity rate.


Assuntos
Displasia Ectodérmica/genética , Ectodisplasinas/genética , Receptor Edar/genética , Proteína de Domínio de Morte Associada a Edar/genética , Mutação , Análise de Sequência de DNA/métodos , Proteínas Wnt/genética , Consanguinidade , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Turquia
8.
EBioMedicine ; 42: 524-531, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31000419

RESUMO

BACKGROUND: Primary Ovarian Insufficiency (POI), a major cause of infertility, affects about 1-3% of women under forty years of age. Although there is a growing list of causal genetic alterations, POI remains mostly idiopathic. METHODS: We performed exome sequencing (WES) of two sisters affected with POI, one unaffected sister and their mother from a consanguineous family. We assessed the impact of the identified MEIOB variant with a minigene assay and by sequencing illegitimate transcripts from the proband's leukocytes. We studied its functional impact on the interaction between MEIOB with its partner SPATA22 and their localization to DNA double-strand breaks (DSB). FINDINGS: We identified a homozygous variant in the last base of exon 12 of MEIOB, which encodes a factor essential for meiotic recombination. This variant was predicted to strongly affect MEIOB pre-mRNA splicing. Consistently, a minigene assay showed that the variant induced exon 12 skipping, which was confirmed in vivo in the proband's leukocytes. Aberrant splicing leads to the production of a C-terminally truncated protein that cannot interact with SPATA22, abolishing their recruitment to DSBs. INTERPRETATION: This truncating MEIOB variant is expected to provoke meiotic defects and a depleted follicular stock, as in Meiob-/- mice. This is the first molecular defect reported in a meiosis-specific single-stranded DNA-binding protein (SSB) responsible for POI. We hypothesise that alterations in other SSB proteins could explain cases of syndromic or isolated ovarian insufficiency. FUND: Université Paris Diderot, Fondation pour la Recherche Médicale, Fondation ARC contre le cancer, Commissariat à l'Energie Atomique and Institut Universitaire de France.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Quebras de DNA de Cadeia Dupla , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Mutação , Insuficiência Ovariana Primária/etiologia , Insuficiência Ovariana Primária/metabolismo , Adolescente , Adulto , Animais , Biomarcadores , Linhagem Celular , Consanguinidade , Feminino , Expressão Gênica , Humanos , Informática/métodos , Camundongos , Linhagem , Insuficiência Ovariana Primária/diagnóstico , Ligação Proteica , Sequenciamento Completo do Exoma , Adulto Jovem
9.
Int J Pediatr Otorhinolaryngol ; 122: 27-34, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30933841

RESUMO

OBJECTIVES: To identify the average age of identification (AOI) and characteristics of Saudi children with sensorineural hearing loss (SNHL). METHODS: Two cross-sectional studies were undertaken. Study A: the medical records of 1166 children aged 0-10 years old who visited the audiology clinics in four hospitals in Riyadh and Dammam during 2015 were reviewed. Study B: 174 carers of children aged 0-12 years who visited the audiology clinics in four hospitals in Riyadh during a three-month period were surveyed. RESULTS: The mean AOI with SNHL in children was 3.2 years (SD = 2.5 years) and 3.1 years (SD = 2.6 years) with 14% and 16% not identified until after primary school age for Studies A and B, respectively. The presence of SNHL was positively associated with parental consanguinity, positive family history of SNHL, history of chemotherapy treatment, brain pathology and prior parental concern regarding their child's hearing. CONCLUSION: AOI of SNHL among Saudi children is deemed high in relation to the likely age of onset, with about 15 in 100 children identified after school age. Childhood hearing screening programmes (at birth and at school entry) should be considered in order to intervene earlier.


Assuntos
Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/epidemiologia , Fatores Etários , Encefalopatias/epidemiologia , Criança , Pré-Escolar , Consanguinidade , Estudos Transversais , Feminino , Perda Auditiva Neurossensorial/genética , Humanos , Lactente , Recém-Nascido , Masculino , Pais , Fatores de Risco , Arábia Saudita/epidemiologia , Inquéritos e Questionários
10.
J Genet ; 982019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30945686

RESUMO

This study evaluates a family with two siblings having severe growth retardation and facial dysmorphism, born to consanguineous normal healthy parents. Affymetrix CytoScan 750K microarray showed a 34-Mb pericentric homozygous region on chromosome 6 for both siblings. CUL7 was one of the 141 genes present in this region. Sanger sequencing of CUL7 gene detected a 2-bp novel deletion in the 15th exon (c.2943_2944delCT of the cDNA). This deletion leads to a frameshift and a premature termination signal much upstream of the wild-type termination signal, leading to a nonsense mediated decay of the mRNA. CUL7 protein plays an important role in formation of 3M complex, ubiquitination, microtubule dynamics and cell cycle regulation. Mutations in CUL7 gene is known to cause a rare 3M syndrome. Information about the novel mutation has been accepted in the ClinVar database with rs1064792895.


Assuntos
Proteínas Culina/genética , Nanismo/genética , Nanismo/patologia , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Mutação , Coluna Vertebral/anormalidades , Criança , Pré-Escolar , Consanguinidade , Feminino , Humanos , Masculino , Prognóstico , Irmãos , Coluna Vertebral/patologia
11.
Hum Genet ; 138(6): 593-600, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30982135

RESUMO

Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. In this study, two Pakistani multiplex consanguineous families with autosomal recessive nonsyndromic PAP were clinically and molecularly evaluated. From both pedigrees, a DNA sample from an affected member underwent exome sequencing. In each family, we identified a segregating frameshift (c.591dupA [p.(Q198Tfs*21)]) and nonsense variant (c.2173A > T [p.(K725*)]) in KIAA0825 (also known as C5orf36). Although KIAA0825 encodes a protein of unknown function, it has been demonstrated that its murine ortholog is expressed during limb development. Our data contribute to the establishment of a catalog of genes important in limb patterning, which can aid in diagnosis and obtaining a better understanding of the biology of polydactyly.


Assuntos
Dedos/anormalidades , Genes Recessivos/genética , Predisposição Genética para Doença/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Polidactilia/genética , Dedos do Pé/anormalidades , Animais , Consanguinidade , Saúde da Família , Feminino , Dedos/patologia , Genótipo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Linhagem , Fenótipo , Polidactilia/patologia , Dedos do Pé/patologia , Sequenciamento Completo do Exoma/métodos
12.
Gene ; 705: 109-112, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31028865

RESUMO

Variants of KCNQ4 are one of the most common causes of dominantly inherited nonsyndromic hearing loss. We investigated a consanguineous family in which two individuals had prelignual hearing loss, apparently inherited in a recessive mode. Whole-exome sequencing analyses demonstrated genetic heterogeneity as variants in two different genes segregated with the phenotype in two branches of the family. Members in one branch were homozygous for a pathogenic variant of TMC1. The other two affected individuals were homozygous for a missense pathogenic variant in KCNQ4 c.872C>T; p.(Pro291Leu). These two individuals had prelingual, progressive moderate to severe hearing loss, while a heterozygous carrier had late onset mild hearing loss. Our work demonstrates that p.Pro291L variant is semi-dominantly inherited. This is the first report of semi-dominance of a KCNQ4 variant.


Assuntos
Surdez/genética , Canais de Potássio KCNQ/genética , Mutação de Sentido Incorreto , Sequenciamento Completo do Exoma/métodos , Idade de Início , Consanguinidade , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença , Humanos , Leucina/genética , Masculino , Linhagem , Prolina/genética
13.
Gene ; 704: 97-102, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30978478

RESUMO

In the current study, we report three cases of Asparagine Synthetase (ASNS) Deficiency from two consanguineous families. Family 1 had two early neonatal deaths due to a novel mutation in the ASNS gene c.788C > T (p.S263F) and both the children presented with microcephaly and one of them had severe intracranial haemorrhage. The proband from the second family was homozygous for c.146G > A (p.R49Q) and manifested myoclonic seizures, developmental delay, coarse hair and diffuse cortical atrophy. Molecular docking studies of both the mutations revealed alteration in the ligand binding site. Till date, 26 mutations were reported in ASNS gene in 29 affected children indicating high degree of genetic heterogeneity and high mortality. Although asparagine depletion is not of diagnostic utility, multiple linear regression model suggested that asparagine levels vary to the extent of 20.6% based on glutamine and aspartate levels and ASNS deficiency results in depletion of asparagine synthesis. ASNS deficiency should be suspected in any neonate with microcephaly and epileptic encephalopathy.


Assuntos
Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/genética , Deficiências do Desenvolvimento/genética , Microcefalia/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Grupo com Ancestrais do Continente Asiático , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/deficiência , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/patologia , Família , Feminino , Humanos , Índia , Lactente , Recém-Nascido , Hemorragias Intracranianas/congênito , Hemorragias Intracranianas/genética , Masculino , Microcefalia/patologia , Técnicas de Diagnóstico Molecular , Morte Perinatal , Convulsões/complicações , Convulsões/genética
14.
Nat Commun ; 10(1): 1477, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30931947

RESUMO

Phenotypic and biochemical categorization of humans with detrimental variants can provide valuable information on gene function. We illustrate this with the identification of two different homozygous variants resulting in enzymatic loss-of-function in LDHD, encoding lactate dehydrogenase D, in two unrelated patients with elevated D-lactate urinary excretion and plasma concentrations. We establish the role of LDHD by demonstrating that LDHD loss-of-function in zebrafish results in increased concentrations of D-lactate. D-lactate levels are rescued by wildtype LDHD but not by patients' variant LDHD, confirming these variants' loss-of-function effect. This work provides the first in vivo evidence that LDHD is responsible for human D-lactate metabolism. This broadens the differential diagnosis of D-lactic acidosis, an increasingly recognized complication of short bowel syndrome with unpredictable onset and severity. With the expanding incidence of intestinal resection for disease or obesity, the elucidation of this metabolic pathway may have relevance for those patients with D-lactic acidosis.


Assuntos
Acidose Láctica/diagnóstico , Lactato Desidrogenases/genética , Ácido Láctico/metabolismo , Mutação com Perda de Função , Síndrome do Intestino Curto/metabolismo , Espasmos Infantis/diagnóstico , Acidose Láctica/genética , Adulto , Animais , Consanguinidade , Diagnóstico Diferencial , Homozigoto , Humanos , Lactente , Lactato Desidrogenases/deficiência , Masculino , Espasmos Infantis/genética , Peixe-Zebra
15.
PLoS Genet ; 15(4): e1008088, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31034465

RESUMO

PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. At the cellular level, PIK3C2A is critical for the formation of cilia and for receptor mediated endocytosis, among other biological functions. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. In particular, the considerable phenotypic overlap, yet distinct features, between this syndrome and Lowe's syndrome, which is caused by mutations in the PI-5-phosphatase OCRL, highlight the key role of PI metabolizing enzymes in specific developmental processes and demonstrate the unique non-redundant functions of each enzyme. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Catarata/genética , Transtornos da Motilidade Ciliar/genética , Nanismo/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Adolescente , Adulto , Criança , Consanguinidade , Feminino , Fibroblastos/metabolismo , Humanos , Masculino , Linhagem , Fenótipo , Adulto Jovem
16.
Eur J Endocrinol ; 180(5): 291-309, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30893644

RESUMO

Context Most of the knowledge on the factors involved in human sexual development stems from studies of rare cases with disorders of sex development. Here, we have described a novel 46, XY complete gonadal dysgenesis syndrome caused by homozygous variants in PPP2R3C gene. This gene encodes B″gamma regulatory subunit of the protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase involved in the phospho-regulation processes of most mammalian cell types. PPP2R3C gene is most abundantly expressed in testis in humans, while its function was hitherto unknown. Patients and methods Four girls from four unrelated families with 46, XY complete gonadal dysgenesis were studied using exome or Sanger sequencing of PPP2R3C gene. In total, four patients and their heterozygous parents were investigated for clinical, laboratory, immunohistochemical and molecular characteristics. Results We have identified three different homozygous PPP2R3C variants, c.308T>C (p.L103P), c.578T>C (p.L193S) and c.1049T>C (p.F350S), in four girls with 46, XY complete gonadal dysgenesis. Patients also manifested a unique syndrome of extragonadal anomalies, including typical facial gestalt, low birth weight, myopathy, rod and cone dystrophy, anal atresia, omphalocele, sensorineural hearing loss, dry and scaly skin, skeletal abnormalities, renal agenesis and neuromotor delay. We have shown a decreased SOX9-Phospho protein expression in the dysgenetic gonads of the patients with homozygous PPP2R3C variants suggesting impaired SOX9 signaling in the pathogenesis of gonadal dysgenesis. Heterozygous males presented with abnormal sperm morphology and impaired fertility. Conclusion Our findings suggest that PPP2R3C protein is involved in the ontogeny of multiple organs, especially critical for testis development and spermatogenesis. PPPR3C provides insight into pathophysiology, as well as emerging as a potential therapeutic target for male infertility.


Assuntos
Disgenesia Gonadal 46 XY/genética , Proteína Fosfatase 2/genética , Espermatogênese/genética , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Anormalidades Congênitas/genética , Consanguinidade , Feminino , Disgenesia Gonadal 46 XY/patologia , Homozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Mutação , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição SOX9/genética , Síndrome , Testículo/embriologia , Testículo/patologia
17.
Gene ; 700: 65-69, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30898718

RESUMO

INTRODUCTION: Adams-Oliver syndrome (AOS) is a rare developmental disorder characterized by the combination of aplasia cutis congenita of the scalp vertex and terminal transverse limb defects. DOCK6 (Dedicator of cytokinesis 6) is one of the six identified AOS genes. METHODS: We performed targeted next-generation sequencing (NGS) of a child with an AOS phenotype. Sanger DNA sequencing further validated her lineal consanguinity. To explore the pathological features of the mutation, a minigene assay was used to investigate the effects of the mutation on splicing. RESULTS: Two compound heterozygous DOCK6 mutations (c.4106+2T>C and c.3063 C>G (p.Y1021*)) were identified in this family, and both mutations have not been reported previously. Sanger DNA sequencing indicated that the mutations were inherited maternally and paternally, respectively. The results of the minigene assay showed that the c.4106+2T>C mutation resulted in aberrant splicing and caused a four-nucleotide insertion in the transcript and a premature stop codon. CONCLUSIONS: Our findings expanded the number of reported cases of this rare disease and the mutation spectrum of DOCK6 mutations, which can serve as the basis for prenatal diagnosis and genetic counseling.


Assuntos
Displasia Ectodérmica/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Deformidades Congênitas dos Membros/genética , Mutação , Dermatoses do Couro Cabeludo/congênito , Análise de Sequência de DNA/métodos , Pré-Escolar , Consanguinidade , Feminino , Genes Recessivos , Heterozigoto , Humanos , Masculino , Linhagem , Fenótipo , Dermatoses do Couro Cabeludo/genética
18.
Mol Vis ; 25: 144-154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820150

RESUMO

Purpose: Primary congenital glaucoma (PCG) is a clinically and genetically heterogeneous disease. The present study was undertaken to find the genetic causes of PCG segregating in 36 large consanguineous Pakistani families. Methods: Ophthalmic examination including fundoscopy, or slit-lamp microscopy was performed to clinically characterize the PCG phenotype. Genomic nucleotide sequences of the CYP1B1 and LTBP2 genes were analyzed with either Sanger or whole exome sequencing. In silico prediction programs were used to assess the pathogenicity of identified alleles. ClustalW alignments were performed to determine evolutionary conservation, and three-dimensional (3D) modeling was performed using HOPE and Phyre2 software. Results: Among the known loci, mutations in CYP1B1 and LTBP2 are the common causes of PCG. Therefore, we analyzed the genomic nucleotide sequences of CYP1B1 and LTBP2, and detected probable pathogenic variants cosegregating with PCG in 14 families. These included the three novel (c.542T>A, c.1436A>G, and c.1325delC) and five known (c.868dupC, c.1168C>T, c.1169G>A, c.1209InsTCATGCCACC, and c.1310C>T) variants in CYP1B1. Two of the novel variants are missense substitutions [p.(Leu181Gln), p.(Gln479Arg)], which replaced evolutionary conserved amino acids, and are predicted to be pathogenic by various in silico programs, while the third variant (c.1325delC) is predicted to cause reading frameshift and premature truncation of the protein. A single mutation, p.(Arg390His), causes PCG in six (~43%) of the 14 CYP1B1 mutations harboring families, and thus, is the most common variant in this cohort. Surprisingly, we did not find any LTBP2 pathogenic variants in the families, which further supports the genetic heterogeneity of PCG in the Pakistani population. Conclusions: In conclusion, results of the present study enhance our understanding of the genetic basis of PCG, support the notion of a genetic modifier of CYP1B1, and contribute to the development of genetic testing protocols and genetic counseling for PCG in Pakistani families.


Assuntos
Citocromo P-450 CYP1B1/genética , Heterogeneidade Genética , Glaucoma/genética , Mutação , Adolescente , Adulto , Idoso , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Criança , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Feminino , Expressão Gênica , Frequência do Gene , Glaucoma/congênito , Glaucoma/patologia , Glaucoma/cirurgia , Humanos , Lactente , Proteínas de Ligação a TGF-beta Latente/genética , Masculino , Pessoa de Meia-Idade , Paquistão , Linhagem , Alinhamento de Sequência , Trabeculectomia/métodos
19.
Clin Chim Acta ; 494: 64-70, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30871974

RESUMO

BACKGROUND: A consanguineous Chinese family was affected by an apparently novel autosomal recessive disorder characterized by cerebellar ataxia, cutaneous photosensitivity, and mild intellectual disability. METHODS: The family was evaluated by homozygosity mapping, haplotype analysis, whole exome sequencing, and candidate gene mutation screening to identify the disease-associated gene and mutation. Bioinformatics methods were used to predict the functional significance of the mutated gene product. ERCC8 mutations and phenotypes were examined. RESULTS: All three patients presented cerebellar ataxia, cutaneous photosensitivity, and mild intellectual disability. Whole genome and candidate region linkage analysis in the consanguineous family revealed a maximum logarithm of the odds score at 5q12.1. This homozygous region was confirmed by homozygosity mapping. The pathogenic missense mutation p.Gly257Arg affecting an evolutionary highly conserved amino acid was identified in ERCC8 at 5q12.1. Integrated application of whole exome sequencing and homozygosity mapping is an efficient approach for gene mapping and mutation identification in consanguineous families. CONCLUSIONS: We identified a novel ERCC8 mutation and new unique disease phenotype. These results also confirmed the genotype-phenotype relationship between mutations in ERCC8 and clinical findings.


Assuntos
Ataxia Cerebelar/genética , Mapeamento Cromossômico , Consanguinidade , Enzimas Reparadoras do DNA/genética , Mutação , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma , China , Feminino , Genótipo , Humanos , Masculino , Linhagem , Fenótipo
20.
Doc Ophthalmol ; 139(1): 11-20, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30927187

RESUMO

PURPOSE: To investigate receptor and post-receptor function in KCNV2 retinopathy [cone dystrophy with supernormal rod electroretinogram (ERG)], using the pupillary light reflex (PLR) and the ERG. METHODS: Two unrelated patients (1 male and 1 female) with molecularly confirmed KCNV2 retinopathy underwent full-field two-color pupillometry testing in one eye, with monitoring of the stimulated eye by an infrared digital camera. Pupillometry stimuli consisted of 1-s duration, short-wavelength (465-nm, blue) and long-wavelength (642-nm, red) stimuli. Pupillometry intensity series were performed under both a dark-adapted condition and a light-adapted condition (on a 0.76-log cd m-2 blue background). The transient PLR, defined as the maximum constriction following flash onset, was measured under all conditions. The melanopsin-mediated sustained constriction was measured 5-7 s following flash offset for the highest flash luminance presented in the dark. Both patients were also tested in one eye with the full-field ERG, including a dark-adapted intensity series and ISCEV standard stimuli. RESULTS: Dark-adapted PLRs were markedly attenuated or extinguished for low-luminance stimuli, but the responses to higher-luminance blue stimuli were within normal limits. Light-adapted PLRs to blue stimuli were generally within normal limits, exceeding the responses to photopically matched red stimuli. Thus, light-adapted responses were consistent with either rod or S-cone mediation of the PLR. Melanopsin-mediated sustained PLRs were within normal limits. ERG showed the characteristic findings previously reported in this condition. Cone-mediated ERG responses were markedly decreased in amplitude. Rod-mediated ERG responses were absent for low-luminance stimuli (- 3 log cd s m-2), but had normal amplitude for stimuli of - 2 log cd s m-2 and above (although none were "supernormal"). The b-wave for the dark-adapted ISCEV standard - 2 log cd s m-2 stimulus was markedly delayed, whereas the b-wave timing was generally normal for higher flash luminances. CONCLUSIONS: The abnormalities measured by pupillometry have a similar pattern to the outer-retinal abnormalities measured by ERG in KCNV2 retinopathy. These findings as well as the normal sustained PLR suggest that inner-retinal function may be preserved in KCNV2 retinopathy and highlight the potential for therapies designed to restore outer-retinal function in these individuals.


Assuntos
Células Fotorreceptoras de Vertebrados/fisiologia , Reflexo Pupilar/fisiologia , Retinite Pigmentosa/fisiopatologia , Adulto , Consanguinidade , Adaptação à Escuridão , Eletrorretinografia , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Estimulação Luminosa , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Retinite Pigmentosa/genética , Opsinas de Bastonetes/metabolismo , Adulto Jovem
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