Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients.

Objective: Limb-girdle muscular dystrophies (LGMDs), one of the most heterogeneous neuromuscular disorders (NMDs), involves predominantly proximal-muscle weakness with >30 genes associated with different subtypes. The clinical-genetic overlap among subtypes and with other NMDs complicate disease-subtype identification lengthening diagnostic process, increases overall costs hindering treatment/clinical-trial recruitment. Currently seven LGMD clinical trials are active but still no gene-therapy-related treatment is available.

Variants of uncertain significance in newborn screening disorders: implications for large-scale genomic sequencing.

Purpose: As exome and genome sequencing using high-throughput sequencing technologies move rapidly into the diagnostic process, laboratories and clinicians need to develop a strategy for dealing with uncertain findings. A commitment must be made to minimize these findings, and all parties may need to make adjustments to their processes. The information required to reclassify these variants is often available but not communicated to all relevant parties.

Detection limit of intragenic deletions with targeted array comparative genomic hybridization.

Background: Pathogenic mutations range from single nucleotide changes to deletions or duplications that encompass a single exon to several genes. The use of gene-centric high-density array comparative genomic hybridization (aCGH) has revolutionized the detection of intragenic copy number variations. We implemented an exon-centric design of high-resolution aCGH to detect single- and multi-exon deletions and duplications in a large set of genes using the OGT 60 K and 180 K arrays.

Parent-of-origin testing for 15q11-q13 gains by quantitative DNA methylation analysis.

The Prader-Willi/Angelman syndrome critical region (PWS/ASCR), located at chromosome 15q11-q13, is associated with several diseases. Absence of paternally expressed genes in this region cause Prader-Willi syndrome (PWS), whereas absence of the maternally expressed UBE3A gene causes Angelman syndrome (AS). In addition, duplications and triplications of this region are also associated with distinct clinical features, indicating that the overexpression of genes within the PWS/ASCR can also lead to distinct phenotypes.

Aberrant firing of replication origins potentially explains intragenic nonrecurrent rearrangements within genes, including the human DMD gene.

Non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), and microhomology-mediated replication-dependent recombination (MMRDR) have all been put forward as mechanisms to explain DNA rearrangements associated with genomic disorders. However, many nonrecurrent rearrangements in humans remain unexplained. To further investigate the mutation mechanisms of these copy number variations (CNVs), we performed breakpoint mapping analysis for 62 clinical cases with intragenic deletions in the human DMD gene (50 cases) and other known disease-causing genes (one PCCB, one IVD, one DBT, three PAH, one STK11, one HEXB, three DBT, one HRPT1, and one EMD cases).

A genome-wide screen for Saccharomyces cerevisiae deletion mutants that affect telomere length.

Telomeres are nucleoprotein structures present at the ends of eukaryotic chromosomes that play a central role in guarding the integrity of the genome by protecting chromosome ends from degradation and fusion. Length regulation is central to telomere function. To broaden our knowledge about the mechanisms that control telomere length, we have carried out a systematic examination of approximately 4,800 haploid deletion mutants of Saccharomyces cerevisiae for telomere-length alterations.