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1.
Hum Genomics ; 15(1): 52, 2021 08 11.
Artículo en Inglés | MEDLINE | ID: mdl-34380564

RESUMEN

BACKGROUND: Familial transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease with significant phenotypic heterogeneity. Its prevalence in Saudi Arabia has not previously been investigated. An existing exome variant database of Saudi individuals, sequenced to globally investigate rare diseases in the population, was mined for TTR variants and filtered for missense mutations resulting in single amino acid changes. A total of 13,906 Saudi exomes from unrelated individuals were analyzed blindly. RESULTS: Three TTR variants known to be associated with ATTR amyloidosis were identified. Additionally, three novel TTR mutations were identified. Structural analysis of the three novel variants suggests that at least two could be amyloidogenic. The most common variant associated with amyloidosis was p.Val142Ile (allele frequency 0.001). Further investigation of these variants and their translation to clinical practice may help to diagnose, monitor, and manage patients with ATTR amyloidosis. CONCLUSION: Multiple TTR variants potentially associated with systemic ATTR amyloidosis were identified in the Saudi population. Early diagnosis and intervention, facilitated by familial genetic testing of patients with ATTR amyloidosis, may benefit in the management of this disease. Early diagnosis could be enhanced through inclusion of ATTR variants in existing population-based screening programs.


Asunto(s)
Neuropatías Amiloides Familiares/genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Prealbúmina/genética , Adolescente , Adulto , Anciano , Neuropatías Amiloides Familiares/epidemiología , Neuropatías Amiloides Familiares/patología , Niño , Minería de Datos , Femenino , Frecuencia de los Genes , Variación Genética/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Arabia Saudita/epidemiología , Adulto Joven
2.
Brain ; 144(3): 769-780, 2021 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-33764426

RESUMEN

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.


Asunto(s)
Ataxia Cerebelosa/genética , Predisposición Genética a la Enfermedad/genética , Trastornos del Neurodesarrollo/genética , Transporte de Proteínas/genética , Proteínas de Transporte Vesicular/genética , Adolescente , Adulto , Animales , Niño , Preescolar , Femenino , Variación Genética , Humanos , Masculino , Linaje , Adulto Joven , Pez Cebra
3.
Endocr Pract ; 26(1): 72-81, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31557081

RESUMEN

Objective: Vitamin D-dependent rickets type 2A (VDDR2A) is a rare autosomal recessive disorder caused by mutations in the vitamin D receptor gene (VDR), leading to end-organ resistance to 1,25-dihydroxyvitamin D3 (1,25[OH]2D3). The objective of this study was to investigate VDR mutations in 11 patients from 8 Turkish-Arab families. Methods: All coding exons and intron-exon boundaries of the VDR gene were amplified by polymerase chain reaction from peripheral leukocyte DNA and sequenced. The effect of splice-site mutations on mRNA splicing was evaluated by a customized VDR mini-gene assay. Results: Homozygous VDR mutations were found in all the patients, including four novel mutations: c.473G>T (p.R158L), c.1-4A>G (IVS3-2A>G), c.755+1G>T, and c.352_356delGACAG (p.D118Sfs*7). The c.1-4A>G mutation was located in the canonical splice acceptor site and 4 base pairs from the original ATG start codon. The mutation resulted in both complete (60% of transcripts) and partial exon 4 skipping (15% of transcripts). The latter was due to activation of a cryptic splice acceptor site and did not disrupt the open reading frame. Both c.755+1G>T and c.352_356delGACAG resulted in frameshifts and a premature stop codon. Clinically, all the patients required continued treatment, except for patient IV-3, who presented with alopecia, hypocalcemia, and increased 1,25(OH)2D3 at 1.5 years of age as a result of the c.1-4A>G mutation. He stopped taking medication at 6 years of age and still maintained normal height and biochemical profile. Conclusion: We have identified four novel VDR mutations. Although canonical splice-site mutations cause premRNA splicing errors that usually lead to a severe disease phenotype, mild disease can also occur due to activation of a cryptic splice site. Abbreviations: 1,25(OH)2D3 = 1,25-dihydroxyvitamin D3 (calcitriol); 25OHD3 = 25-hydroxyvitamin D3; PCR = polymerase chain reaction; PTH = parathyroid hormone; VDDR2A = vitamin D-dependent rickets type 2A; VDR = vitamin D receptor.


Asunto(s)
Raquitismo Hipofosfatémico Familiar/genética , Receptores de Calcitriol/genética , Raquitismo , Niño , Humanos , Lactante , Masculino , Mutación , Fenotipo , Vitamina D
4.
Eur Respir J ; 54(1)2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31073086

RESUMEN

BACKGROUND: Pulmonary fibrosis is one of the leading indications for lung transplantation. The disease, which is of unknown aetiology, can be progressive, resulting in distortion of the extracellular matrix (ECM), inflammation, fibrosis and eventual death. METHODS: 13 patients born to consanguineous parents from two unrelated families presenting with interstitial lung disease were clinically investigated. Nine patients developed respiratory failure and subsequently died. Molecular genetic investigations were performed on patients' whole blood or archived tissues, and cell biological investigations were performed on patient-derived fibroblasts. RESULTS: The combination of a unique pattern of early-onset lung fibrosis (at 12-15 years old) with distinctive radiological findings, including 1) traction bronchiectasis, 2) intralobular septal thickening, 3) shrinkage of the secondary pulmonary lobules mainly around the bronchovascular bundles and 4) early type 2 respiratory failure (elevated blood carbon dioxide levels), represents a novel clinical subtype of familial pulmonary fibrosis. Molecular genetic investigation of families revealed a hypomorphic variant in S100A3 and a novel truncating mutation in S100A13, both segregating with the disease in an autosomal recessive manner. Family members that were either heterozygous carriers or wild-type normal for both variants were unaffected. Analysis of patient-derived fibroblasts demonstrated significantly reduced S100A3 and S100A13 expression. Further analysis demonstrated aberrant intracellular calcium homeostasis, mitochondrial dysregulation and differential expression of ECM components. CONCLUSION: Our data demonstrate that digenic inheritance of mutations in S100A3 and S100A13 underlie the pathophysiology of pulmonary fibrosis associated with a significant reduction of both proteins, which suggests a calcium-dependent therapeutic approach for management of the disease.


Asunto(s)
Pulmón/patología , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/fisiopatología , Proteínas S100/genética , Adolescente , Niño , Salud de la Familia , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Masculino , Mutación , Linaje , Fibrosis Pulmonar/diagnóstico , Arabia Saudita
5.
Genet Med ; 21(1): 185-188, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-29892088

RESUMEN

PURPOSE: Wolf-Hirschhorn syndrome (WHS) is a genomic disorder with a recognizable dysmorphology profile caused by hemizygosity at 4p16.3. Previous attempts have failed to map the minimal critical locus to a single gene, leaving open the possibility that the core phenotypic components of the syndrome are caused by the combined haploinsufficiency of multiple genes. METHODS: Clinical exome sequencing and "reverse" phenotyping. RESULTS: We identified two patients with de novo truncating variants in WHSC1, which maps to the WHS critical locus. The phenotype of these two individuals is consistent with WHS, which suggests that haploinsufficiency of WHSC1 is sufficient to recapitulate the core phenotype (characteristic facies, and growth and developmental delay) of this classic microdeletion syndrome. CONCLUSION: Our study expands the list of microdeletion syndromes that are solved at the single-gene level, and establishes WHSC1 as a disease gene in humans. Given the severe nature of the reported variants, the full phenotypic expression of WHSC1 may be further expanded by future reports of milder variants.


Asunto(s)
Discapacidades del Desarrollo/genética , Predisposición Genética a la Enfermedad , N-Metiltransferasa de Histona-Lisina/genética , Proteínas Represoras/genética , Síndrome de Wolf-Hirschhorn/genética , Preescolar , Deleción Cromosómica , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/patología , Femenino , Haploinsuficiencia/genética , Humanos , Masculino , Fenotipo , Síndrome de Wolf-Hirschhorn/diagnóstico , Síndrome de Wolf-Hirschhorn/patología
6.
Genet Med ; 21(3): 736-742, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30237576

RESUMEN

PURPOSE: Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases. METHODS: Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: We highlight 30 published candidate genes (ACTL6B, ADAM22, AGTPBP1, APC, C12orf4, C3orf17 (NEPRO), CENPF, CNPY3, COL27A1, DMBX1, FUT8, GOLGA2, KIAA0556, LENG8, MCIDAS, MTMR9, MYH11, QRSL1, RUBCN, SLC25A42, SLC9A1, TBXT, TFG, THUMPD1, TRAF3IP2, UFC1, UFM1, WDR81, XRCC2, ZAK) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes (ABCA2, ARL6IP1, ATP8A2, CDK9, CNKSR1, DGAT1, DMXL2, GEMIN4, HCN2, HCRT, MYO9A, PARS2, PLOD3, PREPL, SCLT1, STX3, TXNRD2, WIPI2) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders. CONCLUSIONS: Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.


Asunto(s)
Enfermedad/genética , Genómica/métodos , Análisis de Secuencia de ADN/métodos , Variación Biológica Poblacional/genética , Niño , Preescolar , Diagnóstico , Técnicas y Procedimientos Diagnósticos , Femenino , Pruebas Genéticas/normas , Variación Genética , Genotipo , Herencia/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Homocigoto , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Fenotipo
7.
Brain ; 141(7): 1934-1945, 2018 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-29868776

RESUMEN

The post-translational modification of proteins through the addition of UFM1, also known as ufmylation, plays a critical developmental role as revealed by studies in animal models. The recent finding that biallelic mutations in UBA5 (the E1-like enzyme for ufmylation) cause severe early-onset encephalopathy with progressive microcephaly implicates ufmylation in human brain development. More recently, a homozygous UFM1 variant was proposed as a candidate aetiology of severe early-onset encephalopathy with progressive microcephaly. Here, we establish a locus for severe early-onset encephalopathy with progressive microcephaly based on two families, and map the phenotype to a novel homozygous UFM1 mutation. This mutation has a significantly diminished capacity to form thioester intermediates with UBA5 and with UFC1 (the E2-like enzyme for ufmylation), with resulting impaired ufmylation of cellular proteins. Remarkably, in four additional families where eight children have severe early-onset encephalopathy with progressive microcephaly, we identified two biallelic UFC1 mutations, which impair UFM1-UFC1 intermediate formation with resulting widespread reduction of cellular ufmylation, a pattern similar to that observed with UFM1 mutation. The striking resemblance between UFM1- and UFC1-related clinical phenotype and biochemical derangements strongly argues for an essential role for ufmylation in human brain development. The hypomorphic nature of UFM1 and UFC1 mutations and the conspicuous depletion of biallelic null mutations in the components of this pathway in human genome databases suggest that it is necessary for embryonic survival, which is consistent with the embryonic lethal nature of knockout models for the orthologous genes.


Asunto(s)
Encefalopatías/genética , Proteínas/genética , Enzimas Ubiquitina-Conjugadoras/genética , Adolescente , Adulto , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Encefalopatías/fisiopatología , Niño , Preescolar , Femenino , Células HEK293 , Humanos , Masculino , Microcefalia/genética , Mutación , Linaje , Procesamiento Proteico-Postraduccional , Proteínas/fisiología , Enzimas Activadoras de Ubiquitina/genética , Enzimas Ubiquitina-Conjugadoras/fisiología
8.
Physiol Genomics ; 50(4): 296-297, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29451423

RESUMEN

Over 120 Type 2 diabetes (T2D) loci have been identified from genome-wide association studies (GWAS), mainly from Caucasian populations. Very limited knowledge is available on the Saudi Arabian population. In this study, 122 previously reported T2D-related variants from 84 loci were examined in a Saudi Arabian cohort of 1,578 individuals (659 T2D cases and 919 controls). Eleven single nucleotide polymorphisms (SNPs) corresponding to nine independent loci had a P value <0.05. If a more stringent Bonferroni threshold of P = 4.1 × 10-4 ( = 0.05/122) were applied, none of the SNPs would have reached the significance level. Nine of the SNPs with a P value <0.05 showed similar odds ratios as previously described, but rs11605924 ( CRY2) and rs9470794 ( ZFAND3) were in the opposite direction. This study demonstrates the importance of large-scale GWAS in the Saudi Arabian population to identify ethnicity-specific disease-associated variants.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/genética , Arabia Saudita , Factores de Transcripción/genética
9.
Int J Cancer ; 142(3): 540-546, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-28960316

RESUMEN

Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10-4 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10-9 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.


Asunto(s)
Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Estudios de Casos y Controles , Estudios de Cohortes , Estonia/epidemiología , Finlandia/epidemiología , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido Simple , Sistema de Registros
10.
Hum Mol Genet ; 25(11): 2349-2359, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-27005424

RESUMEN

To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P = 3.15 × 10-8, odds ratio = 1.10, 95% confidence interval = 1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r2 = 0.90, D' = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR]) < 0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Neoplasias Colorrectales/genética , Enfermedades Inflamatorias del Intestino/genética , Proteínas de la Membrana/genética , Proteínas Musculares/genética , Pueblo Asiatico , Neoplasias Colorrectales/patología , Femenino , Pleiotropía Genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Enfermedades Inflamatorias del Intestino/patología , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Población Blanca
11.
BMC Med Genet ; 19(1): 115, 2018 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-29996815

RESUMEN

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder caused by mutations in the CYP21A2. Congenital nephrogenic diabetes insipidus (NDI) is a rare X-linked recessive or autosomal recessive disorder caused by mutations in either AVPR2 or AQP2. Genotype-phenotype discordance caused by genetic mosaicism in CAH patients has not been reported, nor the concomitant CAH and NDI. CASE PRESENTATION: We investigated a patient with concomitant CAH and NDI from a consanguineous family. She (S-1) presented with clitoromegaly at 3 month of age, and polydipsia and polyuria at 13 month of age. Her parents and two elder sisters (S-2 and S-3) were clinically normal, but elevated levels of serum 17-hydroxyprogesterone (17-OHP) were observed in the mother and S-2. The coding region of CYP21A2 and AQP2 were analyzed by PCR-sequencing analysis to identify genetic defects. Two homozygous CYP21A2 mutations (p.R357W and p.P454S) were identified in the proband and her mother and S-2. The apparent genotype-phenotype discordance was due to presence of small amount of wild-type CYP21A2 alleles in S-1, S-2, and their mother's genome, thus protecting them from development of classic form of 21OHD (C21OHD). A homozygous AQP2 mutation (p.A147T) was also found in the patient. The patient was treated with hydrocortisone and hydrochlorothiazide. Her symptoms were improved with normal laboratory findings. The clitoromegaly is persisted. CONCLUSIONS: Genetic mosaicism is a novel mechanism contributing to the genotype-phenotype discordance in 21OHD and small percentage of wild-type CYP21A2 alleles may be sufficient to prevent phenotype development. This is a first report of concurrent 21OHD and NDI caused by simultaneous homozygous CYP21A2 and AQP2 mutations.


Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , Diabetes Insípida Nefrogénica/genética , Adolescente , Adulto , Alelos , Acuaporina 2/genética , Niño , Femenino , Estudios de Asociación Genética/métodos , Genotipo , Humanos , Masculino , Mosaicismo , Mutación/genética , Linaje , Fenotipo , Hermanos , Esteroide 21-Hidroxilasa/genética
12.
Hum Genomics ; 11(1): 28, 2017 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-29137650

RESUMEN

BACKGROUND: Most mitochondrial and cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear genes. Syndromic disorders resulting from mutation of aaRSs genes display significant phenotypic heterogeneity. We expand aaRSs-related phenotypes through characterization of the clinical and molecular basis of a novel autosomal-recessive syndrome manifesting severe mental retardation, ataxia, speech impairment, epilepsy, short stature, microcephaly, hypogonadism, and growth hormone deficiency. RESULTS: A G>A variant in exon 29 of VARS2 (c.3650G>A) (NM_006295) was identified in the index case. This homozygous variant was confirmed by Sanger sequencing and segregated with disease in the family studied. The c.3650G>A change results in alteration of arginine to histidine at residue 1217 (R1217H) of the mature protein and is predicted to be pathogenic. CONCLUSIONS: These findings contribute to a growing list of aaRSs disorders, broadens the spectrum of phenotypes attributable to VARS2 mutations, and provides new insight into genotype-phenotype correlations among the mitochondrial synthetase genes.


Asunto(s)
Epilepsia/genética , Antígenos HLA/genética , Hormona de Crecimiento Humana/deficiencia , Hipogonadismo/genética , Discapacidad Intelectual/genética , Valina-ARNt Ligasa/genética , Estatura/genética , Mapeo Cromosómico , Exoma , Femenino , Genes Recesivos , Trastornos del Crecimiento/genética , Antígenos HLA/metabolismo , Hormona de Crecimiento Humana/genética , Humanos , Masculino , Linaje , Embarazo , Síndrome , Valina-ARNt Ligasa/metabolismo , Adulto Joven
13.
Hum Genomics ; 11(1): 33, 2017 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-29221463

RESUMEN

CORRECTION: After publication of the article [1], it has been brought to our attention that there is a nomenclature issue with this article. At the time of acceptance, the VARS2 mutation was considered equivalent to the VARS2 mutation. However, this has changed so that VARS now only refers to shorter mitochondrial sequence of valyl-tRNA synthesase containing 1093 amino acids. "Therefore, in the context of this article, every usage of "VARS2" should be replaced with "VARS" when referring to the causative variant".

14.
Hum Genomics ; 11(1): 25, 2017 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-29110692

RESUMEN

BACKGROUND: Five affected individuals with syndromic tremulous dystonia, spasticity, and white matter disease from a consanguineous extended family covering a period of over 24 years are presented. A positional cloning approach utilizing genome-wide linkage, homozygozity mapping and whole exome sequencing was used for genetic characterization. The impact of a calmodulin-binding transcription activator 2, (CAMTA2) isoform 2, hypomorphic mutation on mRNA and protein abundance was studied using fluorescent reporter expression cassettes. Human brain sub-region cDNA libraries were used to study the expression pattern of CAMTA2 transcript variants. RESULTS: Linkage analysis and homozygozity mapping localized the disease allele to a 2.1 Mb interval on chromosome 17 with a LOD score of 4.58. Whole exome sequencing identified a G>A change in the transcript variant 2 5'UTR of CAMTA2 that was only 6 bases upstream of the translation start site (c.-6G > A) (NM_001171166.1) and segregated with disease in an autosomal recessive manner. Transfection of wild type and mutant 5'UTR-linked fluorescent reporters showed no impact upon mRNA levels but a significant reduction in the protein fluorescent activity implying translation inhibition. CONCLUSIONS: Mutation of CAMTA2 resulting in post-transcriptional inhibition of its own gene activity likely underlies a novel syndromic tremulous dystonia.


Asunto(s)
Proteínas de Unión al Calcio/genética , Distonía/genética , Transactivadores/genética , Temblor/genética , Regiones no Traducidas 5' , Adolescente , Proteínas de Unión al Calcio/metabolismo , Niño , Cromosomas Humanos Par 17 , Distonía/etiología , Femenino , Humanos , Masculino , Mutación , Linaje , Síndrome , Transactivadores/metabolismo , Temblor/etiología , Adulto Joven
15.
Am J Med Genet A ; 176(3): 715-721, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29383837

RESUMEN

Temtamy syndrome is a syndromic form of intellectual disability characterized by ocular involvement, epilepsy and dysgenesis of the corpus callosum. After we initially mapped the disease to C12orf57, we noted a high carrier frequency of an ancient startloss founder mutation [c.1A>G; p.M1?] in our population, and variable phenotypic expressivity in newly identified cases. This study aims to combine 33 previously published patients with 23 who are described here for the first time to further delineate the phenotype of this syndrome. In addition to the known p.M1? founder, we describe four novel homozygous variants, thus increasing the number of Temtamy syndrome-related C12orf57 variants to seven, all but one predicted to be loss of function. While all patients presented with intellectual disability/developmental delay, the frequency of other phenotypic features was variable: 73.2% (41/56) had epilepsy, 63% (34/54) had corpus callosal abnormalities, 14.5% (8/55) had coloboma, and 16.4% (9/55) had microphthalmia. Our analysis also revealed a high frequency of less recognized features such as congenital heart disease (51.4%), and brain white matter abnormalities (38%, 19/50). We conclude that C12orf57 variants should be considered in the etiology of developmental delay/intellectual disability, even when typical syndromic features are lacking, especially in those who trace their ancestry to Saudi Arabia where a founder C12orf57 mutation is among the most common recessive causes of intellectual disability.


Asunto(s)
Agenesia del Cuerpo Calloso/diagnóstico , Coloboma/diagnóstico , Anomalías Craneofaciales/diagnóstico , Anomalías del Ojo/diagnóstico , Agenesia del Cuerpo Calloso/epidemiología , Agenesia del Cuerpo Calloso/genética , Alelos , Coloboma/epidemiología , Coloboma/genética , Anomalías Craneofaciales/epidemiología , Anomalías Craneofaciales/genética , Anomalías del Ojo/genética , Facies , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Imagen por Resonancia Magnética , Mutación , Fenotipo , Prevalencia
16.
Int J Cancer ; 140(12): 2701-2708, 2017 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-28340513

RESUMEN

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, p = 1.68 × 10-4 ). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92-1.18, p = 0.49), 0.94 (95% CI: 0.84-1.05, p = 0.27), and 0.98 (95% CI: 0.85-1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49-0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.


Asunto(s)
Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad/genética , Hiperlipidemias/genética , Análisis de la Aleatorización Mendeliana/métodos , Polimorfismo de Nucleótido Simple , Colesterol/sangre , Neoplasias Colorrectales/sangre , Estudio de Asociación del Genoma Completo/métodos , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Humanos , Hiperlipidemias/sangre , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Modelos Logísticos , Oportunidad Relativa , Medición de Riesgo , Factores de Riesgo , Triglicéridos/sangre
17.
Clin Endocrinol (Oxf) ; 87(1): 103-112, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28383812

RESUMEN

CONTEXT: Hypophosphataemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3. OBJECTIVE: To investigate underlying genetic defects in patients with hypophosphataemic rickets. METHODS: We analysed genomic DNA from nine unrelated families for mutations in the entire coding region of PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3 by PCR sequencing and copy number analysis. RESULTS: A total of 14 patients were studied. PHEX mutations were identified in 12 patients from seven families. Five of them were novel mutations present in eight patients: c.154G>T (p.E52*), c.401_402insGCCAAA (p.Q134_K135insPK), c.1600C>T (p.P534S), g.22016715_22056805del (40-kb deletion including promoter and exons 1-3) and c.2242_2243delCT (p.L748 fs*48). Four patients had previously reported mutations: c.1768+1G>A and c.1807G>A (p.W602*). Novel CLCN5 (c.1205G>A, p.W402*) and FGF23 (c.526C>G, p.R176G) mutations were found in two patients from the remaining two families. Many of the mutations were de novo: c.154G>T and c.2242_2243delCT in PHEX and c.526C>G in FGF23. Furthermore, we characterized the breakpoint of the novel PHEX g.22016715_22056805del and the c.2242_2243delCT, which is 6 bp from the stop codon, resulting in a frameshift and extension of the reading frame by 42 amino acids. CONCLUSIONS: Novel and de novo mutations are frequent and PHEX mutations are still the most common genetic defects in the Turkish population. Gene copy number analysis should be considered in patients with negative results by conventional PCR-based sequencing analysis. The current study further expands the mutation spectrum underlying HR.


Asunto(s)
Canales de Cloruro/genética , Análisis Mutacional de ADN , Factores de Crecimiento de Fibroblastos/genética , Endopeptidasa Neutra Reguladora de Fosfato PHEX/genética , Raquitismo Hipofosfatémico/genética , Familia , Femenino , Factor-23 de Crecimiento de Fibroblastos , Dosificación de Gen , Humanos , Masculino , Linaje , Turquía
18.
Hum Genomics ; 10(1): 32, 2016 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-27671536

RESUMEN

BACKGROUND: Fifty random genetically unstudied families (limb-girdle muscular dystrophy (LGMD)/myopathy) were screened with a gene panel incorporating 759 OMIM genes associated with neurological disorders. Average coverage of the CDS and 10 bp flanking regions of genes was 99 %. All families were referred to the Neurosciences Clinic of King Faisal Specialist Hospital and Research Centre, Saudi Arabia. Patients presented with muscle weakness affecting the pelvic and shoulder girdle. Muscle biopsy in all cases showed dystrophic or myopathic changes. Our main objective was to evaluate a neurological gene panel as a first-line diagnostic test for LGMD/myopathies. RESULTS: Our panel identified the mutation in 76 % of families (38/50; 11 novel). Thirty-four families had mutations in LGMD-related genes with four others having variants not typically associated with LGMD. The majority of cases had recessive inheritance with homoallelic pathogenic variants (97.4 %, 37/38), as expected considering the high rate of consanguinity in the study population. In one case, we detected a heterozygous mutation in DNAJB responsible for LGMD-1E. Our cohort included seven different subtypes of LGMD2. Mutations of DYSF were the most commonly identified cause of disease followed by that in CAPN3 and FKRP. Non-LGMD myopathies were due to mutations in genes associated with congenital disorder of glycosylation (ALG2), rigid spine muscular dystrophy 1 (SEPN1), inclusion body myopathy2/Nonaka myopathy (GNE), and neuropathy (WNK1). Whole exome sequencing (WES) of patients who remained undiagnosed with the neurological panel did not improve our diagnostic yield. CONCLUSIONS: Our neurological panel achieved a high clinical sensitivity (76 %) and is an effective first-line laboratory test in patients with LGMD and other myopathies. This sensitive, cost-effective, and rapid assay significantly assists clinical practice especially in these phenotypically and genetically heterogeneous disorders. Moreover, the application of the American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP) guidelines applied in the classification of variant pathogenecity provides a clear interpretation for physicians on the relevance of such findings.

19.
Proc Natl Acad Sci U S A ; 111(50): 17953-8, 2014 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-25472840

RESUMEN

Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.


Asunto(s)
ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Enfermedades Carenciales/genética , Hormona Liberadora de Gonadotropina/deficiencia , Síndrome de Kallmann/genética , Fenotipo , Pez Cebra/genética , Animales , Secuencia de Bases , Síndrome CHARGE/genética , Síndrome CHARGE/patología , ADN Helicasas/metabolismo , Proteínas de Unión al ADN/metabolismo , Técnicas de Silenciamiento del Gen , Hormona Liberadora de Gonadotropina/genética , Humanos , Datos de Secuencia Molecular , Mutación Missense/genética , Membrana Otolítica/patología , Estructura Terciaria de Proteína , Análisis de Secuencia de ADN
20.
J Allergy Clin Immunol ; 137(6): 1780-1787, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26915675

RESUMEN

BACKGROUND: Molecular genetics techniques are an essential diagnostic tool for primary immunodeficiency diseases (PIDs). The use of next-generation sequencing (NGS) provides a comprehensive way of concurrently screening a large number of PID genes. However, its validity and cost-effectiveness require verification. OBJECTIVES: We sought to identify and overcome complications associated with the use of NGS in a comprehensive gene panel incorporating 162 PID genes. We aimed to ascertain the specificity, sensitivity, and clinical sensitivity of the gene panel and its utility as a diagnostic tool for PIDs. METHODS: A total of 162 PID genes were screened in 261 patients by using the Ion Torrent Proton NGS sequencing platform. Of the 261 patients, 122 had at least 1 known causal mutation at the onset of the study and were used to assess the specificity and sensitivity of the assay. The remaining samples were from unsolved cases that were biased toward more phenotypically and genotypically complicated cases. RESULTS: The assay was able to detect the mutation in 117 (96%) of 122 positive control subjects with known causal mutations. For the unsolved cases, our assay resulted in a molecular genetic diagnosis for 35 of 139 patients. Interestingly, most of these cases represented atypical clinical presentations of known PIDs. CONCLUSIONS: The targeted NGS PID gene panel is a sensitive and cost-effective diagnostic tool that can be used as a first-line molecular assay in patients with PIDs. The assay is an alternative choice to the complex and costly candidate gene approach, particularly for patients with atypical presentation of known PID genes.


Asunto(s)
Marcadores Genéticos , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/genética , Biología Computacional , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Pruebas Genéticas , Estudio de Asociación del Genoma Completo , Humanos , Síndromes de Inmunodeficiencia/inmunología , Mutación , Polimorfismo de Nucleótido Simple , Flujo de Trabajo
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