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1.
Clin Genet ; 97(6): 915-919, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32112393

RESUMEN

Variants in transcriptional activator Gli Kruppel Family Member 3 (GLI3) have been reported to be associated with several phenotypes including Greig cephalopolysyndactyly syndrome (MIM #175700), Pallister-Hall syndrome (PHS) (MIM #146510), postaxial polydactyly types A1 (PAPA1) and B (PAPB) (MIM #174200), and preaxial polydactyly type 4 (MIM #174700). All these disorders follow an autosomal dominant pattern of inheritance. Hypothalamic hamartomas (MIM 241800) is associated with somatic variants in GLI3. We report a related couple with parents having PAPA1 and PAPB, who had a fetus with a phenotype most compatible with PHS. Molecular analyses demonstrated homozygosity for a pathogenic GLI3 variant (c.1927C > T; p. Arg643*) in the fetus and heterozygosity in the parents. The genetic analysis in this family demonstrates that heterozygosity and homozygosity for the same GLI3 variant can cause a different phenotype. Furthermore, the occurrence of Pallister-Hall-like syndrome in a homozygous patient should be taken into account in genetic counseling of families with PAPA1/PAPB.


Asunto(s)
Anomalías Múltiples/genética , Dedos/anomalías , Proteínas del Tejido Nervioso/genética , Síndrome de Pallister-Hall/genética , Polidactilia/genética , Dedos del Pie/anomalías , Proteína Gli3 con Dedos de Zinc/genética , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/patología , Feto Abortado/diagnóstico por imagen , Feto Abortado/patología , Adulto , Femenino , Dedos/diagnóstico por imagen , Dedos/patología , Heterocigoto , Homocigoto , Humanos , Masculino , Síndrome de Pallister-Hall/complicaciones , Síndrome de Pallister-Hall/diagnóstico por imagen , Síndrome de Pallister-Hall/patología , Linaje , Fenotipo , Polidactilia/complicaciones , Polidactilia/diagnóstico por imagen , Polidactilia/patología , Dedos del Pie/diagnóstico por imagen , Dedos del Pie/patología
2.
Clin Genet ; 95(6): 718-725, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30950035

RESUMEN

Neurodevelopmental delay and intellectual disability (ID) can arise from numerous genetic defects. To date, variants in the EXOSC gene family have been associated with such disorders. Using next-generation sequencing (NGS), known and novel variants in this gene family causing autosomal recessive ID (ARID) have been identified in five Iranian families. By collecting clinical information on these families and comparing their phenotypes with previously reported patients, we further describe the clinical variability of ARID resulting from alterations in the EXOSC gene family, and emphasize the role of RNA processing dysregulation in ARID.


Asunto(s)
Complejo Multienzimático de Ribonucleasas del Exosoma/genética , Genes Recesivos , Discapacidad Intelectual/genética , Niño , Preescolar , Estudios de Cohortes , Consanguinidad , Familia , Femenino , Humanos , Lactante , Discapacidad Intelectual/patología , Discapacidad Intelectual/fisiopatología , Irán , Masculino , Mutación , Linaje , Secuenciación del Exoma
3.
Am J Med Genet A ; 179(8): 1547-1555, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31184804

RESUMEN

Aplasia cutis congenita (ACC) is a heterogeneous group of disorders characterized by localized or widespread absence of skin. ACC can occur isolated or as part of a syndrome. Here we report two consanguineous families, each with two affected offspring. Affected individuals showed widespread ACC while the skin in between had a normal appearance. Ears and nose of the four patients were underdeveloped, otherwise there were no unusual physical characteristics and no internal organ anomalies. "Whole" exome sequencing (WES) of the mother of Family 1 yielded a pathogenic heterozygote variant in ITGB4. The father and healthy offspring were heterozygous for the same variant. WES of the mother of Family 2 yielded a variant in PLEC1. The father and grandmother, who had a history of two offspring with fatal ACC, were heterozygous for the same variant. PLEC1 and ITGB4 have both been previously been reported in association with ACC. We compare findings in earlier reported individuals with variants in ITGB4 and PLEC1, and provide a short summary of other entities going along with ACC.


Asunto(s)
Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Estudios de Asociación Genética , Variación Genética , Integrina beta4/genética , Plectina/genética , Hermanos , Autopsia , Hibridación Genómica Comparativa , Consanguinidad , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Linaje , Fenotipo , Radiografía , Análisis de Secuencia de ADN
4.
NPJ Genom Med ; 9(1): 12, 2024 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-38374194

RESUMEN

Next-generation sequencing (NGS) has been proven to be one of the most powerful diagnostic tools for rare Mendelian disorders. Several studies on the clinical application of NGS in unselected cohorts of Middle Eastern patients have reported a high diagnostic yield of up to 48%, correlated with a high level of consanguinity in these populations. We evaluated the diagnostic utility of NGS-based testing across different clinical indications in 1436 patients from Iran, representing the first study of its kind in this highly consanguineous population. A total of 1075 exome sequencing and 361 targeted gene panel sequencing were performed over 8 years at a single clinical genetics laboratory, with the majority of cases tested as proband-only (91.6%). The overall diagnostic rate was 46.7%, ranging from 24% in patients with an abnormality of prenatal development to over 67% in patients with an abnormality of the skin. We identified 660 pathogenic or likely pathogenic variants, including 241 novel variants, associated with over 342 known genetic conditions. The highly consanguineous nature of this cohort led to the diagnosis of autosomal recessive disorders in the majority of patients (79.1%) and allowed us to determine the shared carrier status of couples for suspected recessive phenotypes in their deceased child(ren) when direct testing was not possible. We also highlight the observations of recessive inheritance of genes previously associated only with dominant disorders and provide an expanded genotype-phenotype spectrum for multiple less-characterized genes. We present the largest mutational spectrum of known Mendelian disease, including possible founder variants, throughout the Iranian population, which can serve as a unique resource for clinical genomic studies locally and beyond.

5.
Arch Iran Med ; 24(5): 364-373, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-34196201

RESUMEN

BACKGROUND: Neurodevelopmental and intellectual impairments are extremely heterogeneous disorders caused by a diverse variety of genes involved in different molecular pathways and networks. Genetic alterations in cilia, highly-conserved organelles with sensorineural and signal transduction roles can compromise their proper functions and lead to so-called "ciliopathies" featuring intellectual disability (ID) or neurodevelopmental disorders as frequent clinical manifestations. Here, we report several Iranian families affected with ID and other ciliopathy-associated features carrying known and novel variants in two ciliary genes; CEP104 and CEP290. METHODS: Whole exome and Targeted exome sequencing were carried out on affected individuals. Lymphoblastoid cell lines (LCLs) derived from the members of affected families were established for two families carrying CEP104 mutations. RNA and protein expression studies were carried out on these cells using qPCR and Western blot, respectively. RESULTS: A novel homozygous variant; NM_025114.3:c.7341_7344dupACTT p.(Ser2449Thrfs*8) and four previously reported homozygous variants; NM_025114.3:c.322C>T p.(Arg108*), NM_025114.3:c.4393C>T p.(Arg1465*), NM_025114.3:c.5668G>T p.(Gly1890*) and NM_025114.3:c.1666dupA p.(Ile556Asnfs*20) were identified in CEP290. In two other families, two novel homozygous variants; NM_014704:c.2356_2357insTT p.(Cys786Phefs*11) and NM_014704:c.1901_1902insT p.(Leu634Phefs*33) were identified in CEP104, another ciliary gene. qPCR and Western blot analyses showed significantly lower levels of CEP104 transcripts and protein in patients compared to heterozygous or normal family members. CONCLUSION: We emphasize on the clinical variability and pleiotropic phenotypes due to variants of these genes. In conclusion, our findings support the pivotal role of these genes resulting in cognitive and neurodevelopmental features.


Asunto(s)
Discapacidad Intelectual , Antígenos de Neoplasias , Proteínas de Ciclo Celular/genética , Proteínas del Citoesqueleto/genética , Exoma , Humanos , Discapacidad Intelectual/genética , Irán , Mutación , Linaje , Secuenciación del Exoma
6.
Iran J Public Health ; 48(10): 1910-1915, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31850270

RESUMEN

BACKGROUND: Diagnosis of hereditary hearing loss (HHL) as a heterogeneous disorder is very important especially in countries with high rates of consanguinity where the autosomal recessive pattern of inheritance is prevalent. Techniques such as next-generation sequencing, a comprehensive genetic test using targeted genomic enrichment and massively parallel sequencing (TGE + MPS), have made the diagnosis more cost-effective. The aim of this study was to determine HHL variants with comprehensive genetic testing in our country. METHODS: Fifty GJB2 negative individuals with HHL were referred to the Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, one of the reference diagnostic genetic laboratories in Iran, during a 3-year period between 2014 and 2017. They were screened with the OtoSCOPE test, the targeted genomic enrichment and massively parallel sequencing (TGE + MPS) platform after a detailed history had been taken along with clinical evaluation. RESULTS: Among 32 out of 50 GJB2 negative patients (64%), 34 known pathogenic and novel variants were detected of which 16 (47%) were novel, identified in 10 genes of which the most prevalent were CDH23, MYO7A and MYO15A. CONCLUSION: These results provide a foundation from which to make appropriate recommendations for the use of comprehensive genetic testing in the evaluation of Iranian patients with hereditary hearing loss.

7.
Arch Iran Med ; 20(9): 617-620, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29048924

RESUMEN

The calcium channel, voltage-dependent, L-type, alpha 1S subunit (CACNA1S) gene encodes a skeletal Ca2+ channel which is involved in calcium-dependent processes such as muscle contraction and neurotransmitter release. Mutations in this gene have been accompanied by hypo- and normokalemic periodic paralysis, thyrotoxic periodic paralysis, and susceptibility to malignant hyperthermia. We report the clinical and genetic findings in a patient diagnosed with metabolic myopathy who had episodic attacks of muscle pain and weakness but with no family background of the disease. Next-generation sequencing (NGS) using a panel targeting metabolic myopathy and myotonia genes identified a de novo heterozygous pathogenic variant c.3724A>G, p.Arg1242Gly, in exon 30 of CACNA1S. As the second report of this variant, this case may broaden the CACNA1S-related disease spectrum to include normokalemic periodic paralysis.


Asunto(s)
Canales de Calcio/genética , Enfermedades Musculares/genética , Canales de Calcio Tipo L , Creatina Quinasa/sangre , Análisis Mutacional de ADN , Humanos , Masculino , Mutación , Secuenciación del Exoma , Adulto Joven
8.
Asian Pac J Cancer Prev ; 14(9): 5011-6, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24175768

RESUMEN

BACKGROUND: Several epidemiological studies have shown associations between colorectal cancer (CRC) risk and type 2 diabetes and obesity. Any effects would be expected to be mediated through the insulin pathway. Therefore it is possible that variants of genes encoding components of the insulin pathway play roles in CRC susceptibility. In this study, we hypothesized that polymorphisms in the genes involving the insulin pathway are associated with risk of CRC. MATERIALS AND METHODS: The associations of four single nucleotide polymorphisms (SNPs) in IGF-I (rs6214), IGFBP-3 (rs3110697), INSR (rs1052371), and IRS2 (rs2289046) genes with the risk of CRC were evaluated using a case-control design with 167 CRC cases and 277 controls by the PCR-RFLP method. RESULTS: Overall, we observed no significant difference in genotype and allele frequencies between the cases and controls for the IGF-I, IGFBP-3, INSR, IRS2 gene variants and CRC before or after adjusting for confounders (age, BMI, sex, and smoking status). However, we observed that the IRS2 (rs2289046) GG genotype compared with AA+AG genotypes has a protective effect for CRC in normal weight subjects (p=0.035, OR=0.259, 95%CI= 0.074-0.907). CONCLUSIONS: These findings do not support plausible associations between polymorphic variations in IGF-I, IGFBP-3, INSR, IRS2 genes and risk of CRC. However, the evidence for a link between the IRS2 (rs2289046) variant and risk of CRC dependent on the BMI of the subjects, requires confirmation in subsequent studies with greater sample size.


Asunto(s)
Antígenos CD/genética , Carcinoma/genética , Neoplasias Colorrectales/genética , Proteínas Sustrato del Receptor de Insulina/genética , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/genética , Receptor de Insulina/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Carcinoma/epidemiología , Estudios de Casos y Controles , Neoplasias Colorrectales/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Irán/epidemiología , Masculino , Persona de Mediana Edad , Obesidad/epidemiología , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple , Factores Protectores , Factores de Riesgo , Adulto Joven
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