Mutations in the potassium channel subunit gene KCNT1 have been identified during the past three years in patients with neurological disorders including nocturnal frontal lobe epilepsy, epileptic encephalopathies and white matter diseases. KCNT1 mutations have also been linked to cardiac arrhythmias. In this review we describe the current knowledge of the KCNT1 gene and its […]
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Gene editing of DNAH11 restores normal cilia motility in primary ciliary dyskinesia
Primary ciliary dyskinesia (PCD) is a genetic disorder that severely affects the quality of life, manifests early in life, and leads to premature death. PCD is characterized by dysfunction of motile cilia that causes progressive impairment of pulmonary function and severe respiratory infections. There is no specific cure. This study demonstrates that gene dysfunction causing […]
Deletions of 5′ HOXC genes are associated with lower extremity malformations, including clubfoot and vertical talus
Deletions of the HoxC gene cluster result in variable phenotypes in mice, but have been rarely described in humans. Here, we report chromosome 12q13.13 microdeletions ranging from 13-175 kb and involving the 5’ HOXC genes in four families segregating congenital lower limb malformations, including clubfoot, vertical talus and hip dysplasia. We identified reduced HOXC gene […]
CRISPR-Cas9 for medical genetic screens: applications and future perspectives
CRISPR-Cas9 (Clustered regularly interspaced short palindromic repeats-associated nuclease 9) systems, the versatile and convenient tools for genome editing and epigenome modulation, have been applied in various genomic screen studies. Compared with conventional RNAi screens, CRISPR screens incur less off-target effects and can be used in multiple formats and can target both coding and noncoding regions […]
Local genotype influences DNA methylation at two asthma-associated regions, 5q31 and 17q21, in a founder effect population
Chromosome 5q31 and 17q12-q21 regions show strong genetic association with asthma, however not everyone who carries a risk allele is affected. We hypothesized that inter-individual variation in promoter DNA methylation may modify the risk of asthma development. DNA methylation levels in blood of asthmatic and non-affected individuals from the Saguenay-Lac-Saint-Jean asthma familial collection were analyzed. […]
Disruption of Golgi morphology and altered protein glycosylation in PLA2G6-associated neurodegeneration
Mutations in the gene PLA2G6 cause neurodegeneration by a yet undefined mechanism. In this study we analyzed the Golgi and glycosylation in cultured skin fibroblasts in three patients with PLA2G6-associated neurodegeneration (PLAN). Although each patient had different mutations, all had altered Golgi morphology and protein O-linked glycosylation that were rescued by overexpression of wild type […]
The Regulatory Element READ1 Epistatically Influences Reading and Language, with both Deleterious and Protective Alleles
Dyslexia and Language Impairment (LI) are common learning disabilities that make written and spoken language difficult to process for affected individuals. Both disorders have a strong genetic component, but inheritance is complex and individual risk variants have been difficult to identify. In this study, we show that alleles of READ1, a genetic variant associated with […]
Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases
Familial Adenomatous Polyposis (FAP), caused by germline mutations in the tumor suppressor gene APC, is one of the most common types of hereditary colorectal cancer. However, in a considerable fraction of families the disease remains unexplained. This is the first study which comprehensively explored the impact of low-level APC mutational mosaicism. Multiple colorectal polyps in […]
Intellectual ability in tuberous sclerosis complex correlates with predicted effects of mutations on TSC1 and TSC2 proteins
Tuberous sclerosis complex (TSC) is a genetic disorder with a birth incidence of 1 in 6000, which is quite common for a ‘rare’ genetic disease. The two genes, their proteins and intracellular signalling pathways have been identified. TSC leads to multi-system involvement including benign tumours and very high rates of TSC-associated neuropsychiatric disorders. Some people […]
Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family
We investigated a large consanguineous family from Pakistan comprising multiple affected individuals with intellectual disability and epilepsy. Using a combination of next-generation and classical sequencing methods, we identified a bi-allelic missense mutation p.R53Q in the LMAN2L gene only in the patients and not in the unaffected family members. LMAN2L encodes for a protein playing a […]