Search results for "MUTATION"

Italian familial defective apolipoprotein B patients share a unique haplotype with other Caucasian patients.

2001

Familial defective apolipoprotein (apo) B-100 together with familial hypercholesterolemia are the two common genetic conditions that cause hypercholesterolemia. Familial defective apolipoprotein B-100 is due to mutations around codon 3500 of the apo B gene. The most-characterized mutation is a G>A transition at nucleotide 10,708 that results in the substitution of arginine by glutamine at codon 3500 (Apo B Arg3500Gln). Two other mutations are caused by a C>T transition, one at nucleotide 10,800 (Apo B Arg3531Cys) and the other at nucleotide 10,707 (apo B Arg3500Trp). In the present study we describe three new Italian cases of familial defective apolipoprotein B-100 (Apo B Arg3500Gln), one f…

PIK3R1 Mutations Cause Syndromic Insulin Resistance with Lipoatrophy

2013

International audience; Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting wi…

Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant.

2021

Almost half of all individuals affected by intellectual disability (ID) remain undiagnosed. In the Solve-RD project, exome sequencing (ES) datasets from unresolved individuals with (syndromic) ID (n = 1,472 probands) are systematically reanalyzed, starting from raw sequencing files, followed by genome-wide variant calling and new data interpretation. This strategy led to the identification of a disease-causing de novo missense variant in TUBB3 in a girl with severe developmental delay, secondary microcephaly, brain imaging abnormalities, high hypermetropia, strabismus and short stature. Interestingly, the TUBB3 variant could only be identified through reanalysis of ES data using a genome-wi…

A G613A missense in the Hutchinson's progeria lamin A/C gene causes a lone, autosomal dominant atrioventricular block.

2014

Background LMNA/C mutations have been linked to the premature aging syndrome Hutchinson’s progeria, dilated cardiomyopathy 1A, skeletal myopathies (such as the autosomal dominant variant of Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy), Charcot-Marie-Tooth disorder type 2B1, mandibuloacral dysplasia, autosomal dominant partial lipodystrophy, and axonal neuropathy. Atrioventricular block (AVB) can be associated with several cardiac disorders and it can also be a highly heritable, primitive disease. One of the most common pathologies associated with AVB is dilated cardiomyopathy (DCM), which is characterized by cardiac dilatation and reduced systolic function. In this …

2014

In a subset of inherited retinal degenerations (including cone, cone-rod, and macular dystrophies), cone photoreceptors are more severely affected than rods; ABCA4 mutations are the most common cause of this heterogeneous class of disorders. To identify retinal-disease-associated genes, we performed exome sequencing in 28 individuals with “cone-first” retinal disease and clinical features atypical for ABCA4 retinopathy. We then conducted a gene-based case-control association study with an internal exome data set as the control group. TTLL5, encoding a tubulin glutamylase, was highlighted as the most likely disease-associated gene; 2 of 28 affected subjects harbored presumed loss-of-function…

Rapid screening of the LDL receptor point mutation FH-Genoa/Palermo

1999

The LDL-receptor gene point mutation FH-Genoa/Palermo is the most frequent mutation responsible for Familial Hypercholesterolemia in Sicily. The mutation does not introduce or abolish any useful restriction site. We establish a GeneComb™-based strategy to identify this mutation in a population of Sicilian unrelated clinically diagnosed FH probands. The method was very sensitive and specific; 12 out of 90 (13.3%) unrelated FH probands were found to carry the FH-Genoa/Palermo mutation. According to these results, the FH-Genoa/Palermo is the more frequent LDL-receptor gene mutation among the Sicilian FH patients. Moreover FH-Genoa/Palermo is the mutation cluster to date more represented in Sou…

Molecular genetics of familial hypercholesterolemia in Spain: Ten novel LDLR mutations and population analysis

2001

Mutations underlying FH in Spain are largely unknown because only a few and limited surveys have been carried out on Spanish FH patients up to now. To gain information on this issue, we have analysed a group of 113 unrelated Spanish FH patients from an eastern area of Spain (Valencian Community). We have screened the LDLR gene by Southern blot and PCR-SSCP analysis to detect large rearrangements and small mutations, respectively. In addition, we have screened the Apo B gene for mutations known to cause FDB by PCR-SSCP analysis. We have identified a total of 47 different mutations in the LDLR gene (5 large rearrangements, and 42 small mutations, which were characterized by DNA sequencing), 1…

Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia.

2006

Patients homozygous or Compound heterozygous for LDLR mutations or double heterozygous for LDLR and apo B R3500Q mutation have higher LDL-C levels. more extensive xanthomatosis and more severe premature coronary disease (pCAD) than simple heterozygotes for mutations in either these genes or for missense mutations in PCSK9 gene. It is not known whether combined mutations in LDLR and PKCS9 are associated with such a severe phenotype. We sequenced Apo B and PCSK9 genes in two patients with the clinical diagnosis of homozygous FH who were heterozygous for LDLR gene mutations. Proband Z.P. (LDL-C 13.39 mmol/L and pCAD) was heterozygous for an LDLR mutation (p.E228K) inherited from her father (LD…

BBS1 Mutations in a Wide Spectrum of Phenotypes Ranging From Nonsyndromic Retinitis Pigmentosa to Bardet-Biedl Syndrome

2012

OBJECTIVE: To investigate the involvement of the Bardet-Biedl syndrome (BBS) gene BBS1 p.M390R variant in nonsyndromic autosomal recessive retinitis pigmentosa (RP). METHODS: Homozygosity mapping of a patient with isolated RP was followed by BBS1 sequence analysis. We performed restriction fragment length polymorphism analysis of the p.M390R allele in 2007 patients with isolated RP or autosomal recessive RP and in 1824 ethnically matched controls. Patients with 2 BBS1 variants underwent extensive clinical and ophthalmologic assessment. RESULTS: In an RP proband who did not fulfill the clinical criteria for BBS, we identified a large homozygous region encompassing the BBS1 gene, which carrie…

Linkage analysis and disease models in benign familial infantile seizures: a study of 16 families.

2006

Summary: Purpose: Benign familial infantile seizures (BFIS) is a genetically heterogeneous condition characterized by partial seizures, onset age from 3 to 9 months, and favorable outcome. BFIS loci were identified on chromosomes 19q12-13.1 and 16p12-q12, allelic to infantile convulsions and choreathetosis. The identification of SCN2A mutations in families with only infantile seizures indicated that BFNIS and BFIS may show overlapping clinical features. Infantile seizures also were in a family with familial hemiplegic migraine and mutations in the ATP1A2 gene. We have examined the heterogeneous genetics of BFIS by means of linkage analysis. Methods: Sixteen families were examined. Probands …