Human Molecular Genetics

Canine RPGRIP1-cone-rod dystrophy (CRD), a model for human inherited retinal diseases (IRDs), was originally identified as autosomal recessive early-onset blindness. However, later studies revealed extensive phenotypic variability among RPGRIP1 mutants. This led to the identification of a homozygous MAP9 variant as a modifier associated with early-onset disease. Based on further phenotypic variation affecting cone photoreceptor function, we report mapping of L3 as an additional modifier locus, within a 4.1-Mb locus on canine chromosome 30...

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No abstract text is available yet for this article.

Genome-wide association studies (GWAS) have successfully identified associations for cervical cancer, but the underlying mechanisms of cervical biology and pathology remain uncharacterised. Our GWAS meta-analyses fill this gap, as we characterise the genetic architecture of cervical phenotypes, including cervical ectropion, cervicitis, cervical dysplasia, as well as up to 9229 cases and 490 304 controls for cervical cancer from diverse ancestries. Leveraging latest computational methods and gene expression data, we refine the association signals for cervical cancer and propose potential causal variants and genes at each locus...

BACKGROUND: To understand the shared genetic basis between colorectal cancer (CRC) and other cancers and identify potential pleiotropic loci for compensating the missing genetic heritability of CRC. METHODS: We conducted a systematic genome-wide pleiotropy scan to appraise associations between cancer-related genetic variants and CRC risk among European populations. SNP-set analysis was performed using data from the UK Biobank and the Study of Colorectal Cancer in Scotland (10 039 CRC cases and 30 277 controls) to evaluate the overlapped genetic regions for susceptibility of CRC and other cancers...

In humans, mutations in calmodulin cause cardiac arrhythmia. These mutations disrupt the ability of calmodulin to sense calcium concentrations and correctly regulate two central calcium channels, together obstructing heart rhythm. This correlation is well established, but also surprising since calmodulin is expressed in all tissues and interacts with hundreds of proteins. Until now, most studies have focused on cardiac cell function and regulation of specific cardiac targets, and thus potential other effects of these mutations have largely been unexplored...

Recessive variants in the oxidoreductase PYROXD1 are reported to cause a myopathy in 22 affected individuals from 15 families. Here we describe two female probands from unrelated families presenting with features of a congenital connective tissue disorder including osteopenia, blue sclera, soft skin, joint hypermobility and neuromuscular junction dysfunction in addition to known features of PYROXD1 myopathy including respiratory difficulties, weakness, hypotonia and oromotor dysfunction. Proband AII:1 is compound heterozygous for the recurrent PYROXD1 variant Chr12 (GRCh38):g...

Barth syndrome is an X-linked disorder caused by loss-of-function mutations in Tafazzin (TAZ), an acyltransferase that catalyzes remodeling of cardiolipin, a signature phospholipid of the inner mitochondrial membrane. Patients develop cardiac and skeletal muscle weakness, growth delay, and neutropenia, although phenotypic expression varies considerably between patients. Taz knockout mice recapitulate many of the hallmark features of the disease. We used mouse genetics to test the hypothesis that genetic modifiers alter the phenotypic manifestations of Taz inactivation...

Von Hippel-Lindau (VHL) disease is an autosomal dominant, inherited syndrome with variants in the VHL gene, causing predisposition to multi-organ neoplasms with vessel abnormality. Germline variants in VHL can be detected in 80-90% of patients clinically diagnosed with VHL disease. Here, we summarize the results of genetic tests for 206 Japanese VHL families, and elucidate the molecular mechanisms of VHL disease, especially in variant-negative unsolved cases. Of the 206 families, genetic diagnosis was positive in 175 families (85%), including 134 families (65%) diagnosed by exon sequencing (15 novel variants) and 41 (20%) diagnosed by MLPA (one novel variant)...

No abstract text is available yet for this article.

No abstract text is available yet for this article.

Citrin Deficiency (CD) is an inborn error of metabolism caused by loss-of-function of the mitochondrial aspartate/glutamate transporter, CITRIN, which is involved in both the urea cycle and malate aspartate shuttle. Patients with CD develop hepatosteatosis and hyperammonemia but there is no effective therapy for CD. Currently, there are no animal models that faithfully recapitulate the human CD phenotype. Accordingly, we generated a CITRIN knockout HepG2 cell line using CRISPR/Cas 9 genome editing technology to study metabolic and cell signaling defects in CD...

The eye and brain are composed of elaborately organized tissues, development of which is supported by spatiotemporally precise expression of a number of transcription factors and developmental regulators. Here we report the molecular and genetic characterization of Integrator complex subunit 15 (INTS15). INTS15 was identified in search for the causative gene(s) for an autosomal-dominant eye disease with variable individual manifestation found in a large pedigree. While homozygous Ints15 knockout mice are embryonic lethal, mutant mice lacking a small C-terminal region of Ints15 show ocular malformations similar to the human patients...

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Zinc is an essential trace mineral. Dietary zinc deficiency results in stunted growth, skin lesions, hypogonadism, and frequent infections in humans. Mice genetically lacking Slc30a7 suffer from mild zinc deficiency and are prone to development of prostate cancer and insulin resistance. Disease-causing variants or mutations in the human SLC30A7 (ZNT7) gene have not been previously reported. Here we describe two-boy siblings from a French family with stunted growth, testicular hypoplasia, and bone marrow failure...

Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene panel or whole exome sequencing. In this study, we aimed to investigate the contributions of structural variants (SVs) to settling the molecular diagnosis of IRD with whole-genome sequencing (WGS). A cohort of 755 IRD patients whose pathogenic mutations remain undefined was subjected to WGS. Four SV calling algorithms including include MANTA, DELLY, LUMPY, and CNVnator were used to detect SVs throughout the genome...

SURF1 deficiency (OMIM # 220110) causes Leigh syndrome (LS, OMIM # 256000), a mitochondrial disorder typified by stress-induced metabolic strokes, neurodevelopmental regression, and progressive multisystem dysfunction. Here, we describe two novel surf1-/- zebrafish knockout models generated by CRISPR/Cas9 technology. While gross larval morphology, fertility, and survival into adulthood appeared unaffected, surf1-/- mutants manifested adult-onset ocular anomalies and decreased swimming activity, and classical biochemical hallmarks of human SURF1 disease, including reduced complex IV expression and enzymatic activity and increased tissue lactate...

Patient mutations have been identified throughout dynamin-related protein 1 (Drp1), the key protein mediator of mitochondrial fission. These changes generally impact young children and often result in severe neurological defects and, in some instances, death. Until now, the underlying functional defect leading to patient phenotypes has been largely speculative. We therefore analyzed six disease-associated mutations throughout the GTPase and middle domains of Drp1. The middle domain (MD) plays a role in Drp1 oligomerization, and three mutations in this region were predictably impaired in self-assembly...

Testing the effect of rare variants on phenotypic variation is difficult due to the need for extremely large cohorts to identify associated variants given expected effect sizes. An alternative approach is to investigate the effect of rare genetic variants on DNA methylation (DNAm) as effect sizes are expected to be larger for molecular traits compared to complex traits. Here, we investigate DNAm in healthy ageing populations-the Lothian Birth Cohorts of 1921 and 1936 and identify both transient and stable outlying DNAm levels across the genome...

Facial dysmorphology is a hallmark of 22q11.2 Deletion Syndrome (22q11DS). Nearly all affected individuals have facial features characteristic of the syndrome: a vertically-long face with broad nasal bridge, narrow palpebral fissures and mild micrognathia, sometimes accompanied by facial skeletal and oropharyngeal anomalies. Despite the frequency of craniofacial dysmorphology due to 22q11.2 deletion, there is still incomplete understanding of the contribution of individual 22q11 genes to craniofacial and oropharyngeal development...