Use of TaqI digestion may lead to incorrect molecular diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

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Gene symbol: PLP. Disease: Pelizaeus-Merzbacher disease.

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Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacer disease

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Localization of the gene (or genes) for a syndrome with X-linked mental retardation, ataxia, weakness, hearing impairment, loss of vision and a fatal course in early childhood

Contains fulltext : 24257___.PDF (publisher's version ) (Open Access

Exon copy number alterations of the CHD7 gene are not a major cause of CHARGE and CHARGE-like syndrome.

Item does not contain fulltextCHARGE syndrome is a multiple congenital anomaly syndrome caused by mutations in the CHD7 gene. Mutations in this gene are found in 60-70% of patients suspected of having CHARGE syndrome. However, if only typical CHARGE patients are taken into account, mutations in the CHD7 gene are found in over 90% of cases. The remaining 10% might be caused by hitherto undetected alterations of the CHD7 gene, including whole exon duplications and deletions that are missed by the currently used diagnostic procedures. Therefore we looked for these kinds of alterations by multiplex ligation-dependent probe amplification in 54 patients suspected of having CHARGE syndrome without a CHD7 mutation. In one patient a partial deletion of the CHD7 gene (exons 13-38) was identified, while in the other patients no abnormalities were found. The frequency of exon deletions in our cohort was 1.9% (1/54) and 5.6% (1/18) in all patients and in typical CHARGE patients, respectively. We conclude that exon copy number alterations of the CHD7 gene are not a major cause of CHARGE and CHARGE-like syndrome

The efficacy of microarray screening for autosomal recessive retinitis pigmentosa in routine clinical practice

Contains fulltext : 154175.pdf (publisher's version ) (Open Access)PURPOSE: To determine the efficacy of multiple versions of a commercially available arrayed primer extension (APEX) microarray chip for autosomal recessive retinitis pigmentosa (arRP). METHODS: We included 250 probands suspected of arRP who were genetically analyzed with the APEX microarray between January 2008 and November 2013. The mode of inheritance had to be autosomal recessive according to the pedigree (including isolated cases). If the microarray identified a heterozygous mutation, we performed Sanger sequencing of exons and exon-intron boundaries of that specific gene. The efficacy of this microarray chip with the additional Sanger sequencing approach was determined by the percentage of patients that received a molecular diagnosis. We also collected data from genetic tests other than the APEX analysis for arRP to provide a detailed description of the molecular diagnoses in our study cohort. RESULTS: The APEX microarray chip for arRP identified the molecular diagnosis in 21 (8.5%) of the patients in our cohort. Additional Sanger sequencing yielded a second mutation in 17 patients (6.8%), thereby establishing the molecular diagnosis. In total, 38 patients (15.2%) received a molecular diagnosis after analysis using the microarray and additional Sanger sequencing approach. Further genetic analyses after a negative result of the arRP microarray (n = 107) resulted in a molecular diagnosis of arRP (n = 23), autosomal dominant RP (n = 5), X-linked RP (n = 2), and choroideremia (n = 1). CONCLUSIONS: The efficacy of the commercially available APEX microarray chips for arRP appears to be low, most likely caused by the limitations of this technique and the genetic and allelic heterogeneity of RP. Diagnostic yields up to 40% have been reported for next-generation sequencing (NGS) techniques that, as expected, thereby outperform targeted APEX analysis

Molecular genetic analysis of retinitis pigmentosa in Indonesia using genome-wide homozygosity mapping

Contains fulltext : 98108.pdf (publisher's version ) (Open Access)PURPOSE: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous retinal disorder. Despite tremendous knowledge about the genes involved in RP, little is known about the genetic causes of RP in Indonesia. Here, we aim to identify the molecular genetic causes underlying RP in a small cohort of Indonesian patients, using genome-wide homozygosity mapping. METHODS: DNA samples from affected and healthy individuals from 14 Indonesian families segregating autosomal recessive, X-linked, or isolated RP were collected. Homozygosity mapping was conducted using Illumina 6k or Affymetrix 5.0 single nucleotide polymorphism (SNP) arrays. Known autosomal recessive RP (arRP) genes residing in homozygous regions and X-linked RP genes were sequenced for mutations. RESULTS: In ten out of the 14 families, homozygous regions were identified that contained genes known to be involved in the pathogenesis of RP. Sequence analysis of these genes revealed seven novel homozygous mutations in ATP-binding cassette, sub-family A, member 4 (ABCA4), crumbs homolog 1 (CRB1), eyes shut homolog (Drosophila) (EYS), c-mer proto-oncogene tyrosine kinase (MERTK), nuclear receptor subfamily 2, group E, member 3 (NR2E3) and phosphodiesterase 6A, cGMP-specific, rod, alpha (PDE6A), all segregating in the respective families. No mutations were identified in the X-linked genes retinitis pigmentosa GTPase regulator (RPGR) and retinitis pigmentosa 2 (X-linked recessive; RP2). CONCLUSIONS: Homozygosity mapping is a powerful tool to identify the genetic defects underlying RP in the Indonesian population. Compared to studies involving patients from other populations, the same genes appear to be implicated in the etiology of recessive RP in Indonesia, although all mutations that were discovered are novel and as such may be unique for this population

Hearing impairment in Dutch patients with connexin 26 (GJB2) and connexin 30 (GJB6) mutations.

Contains fulltext : 47759.pdf (publisher's version ) (Closed access)OBJECTIVE: Despite the identification of mutations in the connexin 26 (GJB2) gene as the most common cause of recessive nonsyndromic hearing loss, the pattern of hearing impairment with these mutations remains inconsistent. Recently a deletion encompassing the GJB6 gene was identified and hypothesized to also contribute to hearing loss. We hereby describe the hearing impairment in Dutch patients with biallelic connexin 26 (GJB2) and GJB2+connexin 30 (GJB6) mutations. METHODS: The audiograms of patients who were screened for GJB2 and GJB6 mutations were analysed retrospectively. Standard statistical testing was done for symmetry and shape, while repeated measurement analysis was used to assess the relation between mutation and severity. Progression was also studied via linear regression analysis. RESULTS: Of 222 hearing-impaired individuals, 35 exhibited sequence variations; of these 19 had audiograms for study. Hearing loss in patients with biallelic "radical" (i.e. deletions, nonsense and splice site) mutations was significantly worse than in the wild type and heterozygotes (SAS proc GENMOD, p=0.013). The presence of at least one missense mutation in compound heterozygotes tends to lead to better hearing thresholds compared to biallelic radical mutations (p=0.08). One patient with the [35delG]+[del(GJB6-D13S1830)] genotype was severely impaired. Non-progressive hearing impairment was demonstrated in five 35delG homozygotes in individual longitudinal analyses. However a patient with the [299A>C]+[416G>A] genotype showed significant threshold progression in the lower frequencies. Findings on asymmetry and shape were inconclusive. CONCLUSIONS: Our data support the hypothesis that severity is a function of genotype and its effect on the amino acid sequence. A bigger cohort is required to establish non-progressivity more definitively

Clinical and molecular evaluation of probands and family members with familial exudative vitreoretinopathy.

Contains fulltext : 79536.pdf (publisher's version ) (Closed access)PURPOSE: To describe the ophthalmic characteristics and to identify the molecular cause of FEVR in a cohort of Dutch probands and their family members. METHODS: Twenty families with familial exudative vitreoretinopathy (FEVR) comprising 83 affected and nonaffected individuals were studied. Based on the presence of an avascular zone, the clinical diagnosis was made and biometric data of the posterior pole of 57 patients and family members were obtained by the analysis of fundus photographs and compared with the data of 40 controls. The FZD4, LRP5, and NDP genes were screened for mutations in one affected individual per family. The segregation of the gene variants was studied in the corresponding families. RESULTS: Forty of 83 individuals showed an avascular zone, the most evident clinical sign of FEVR, five showed major signs of FEVR, and 38 persons were not clinically affected. Compared with the control subjects the patients with FEVR had a significantly larger disc-to-macula distance and a significantly smaller optic disc. In 8 of 20 families, a FZD4 mutation was identified, in 2 a mutation in the LRP5 gene, and in 2 a mutation in the NDP gene. Three known and five novel mutations were identified. Nonpenetrance was observed in 26% of the mutation carriers. CONCLUSIONS: Significant anatomic differences were identified between the eyes of patients with FEVR with an avascular zone, when compared with those of the control subjects. In patients with an avascular zone, the optic disc was smaller and the disc-to-macula distance larger than in the control subjects. In 60% of the probands, mutations were identified in one of the three known FEVR genes