Genetic Modifiers of Mendelian Monogenic Collagen IV Nephropathies in Humans and Mice.

Familial hematuria is a clinical sign of a genetically heterogeneous group of conditions, accompanied by broad inter- and intrafamilial variable expressivity. The most frequent condition is caused by pathogenic (or likely pathogenic) variants in the collagen-IV genes, . Pathogenic variants in are responsible for the severe X-linked glomerulopathy, Alport syndrome (AS), while homozygous or compound heterozygous variants in the or the gene cause autosomal recessive AS.

The 2019 and 2021 International Workshops on Alport Syndrome.

In 1927 Arthur Cecil Alport, a South African physician, described a British family with an inherited form of kidney disease that affected males more severely than females and was sometimes associated with hearing loss. In 1961, the eponymous name Alport syndrome was adopted. In the late twentieth century three genes responsible for the disease were discovered: , , and encoding for the α3, α4, α5 polypeptide chains of type IV collagen, respectively.

Guidelines for Genetic Testing and Management of Alport Syndrome.

Genetic testing for pathogenic variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney function impairment. Alport syndrome experts now advocate genetic testing for persistent hematuria, even when a heterozygous pathogenic or is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that or heterozygotes do not act as kidney donors.

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.

Background: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.

Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP.

Goldberg-Shprintzen syndrome (GOSHS) is caused by loss of function variants in the kinesin binding protein gene (KIFBP). However, the phenotypic range of this syndrome is wide, indicating that other factors may play a role. To date, 37 patients with GOSHS have been reported.

Atypical Neurogenesis in Induced Pluripotent Stem Cells From Autistic Individuals.

Background: Autism is a heterogeneous collection of disorders with a complex molecular underpinning. Evidence from postmortem brain studies have indicated that early prenatal development may be altered in autism. Induced pluripotent stem cells (iPSCs) generated from individuals with autism with macrocephaly also indicate prenatal development as a critical period for this condition.

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism.

Correction: A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome.

Purpose: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1).

Methods: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism.

Correction: Delivering genomic medicine in the UK National Health Service: a systematic review and narrative synthesis.

In subsection "Genetics/genomics specialists" sentence beginning "Five…" cited reference 32 (Schwarze et al. 2018) and should have been reference 34 (Carroll et al. 2016).

Delivering genomic medicine in the United Kingdom National Health Service: a systematic review and narrative synthesis.

Purpose: We sought to assess the readiness of the United Kingdom (UK) National Health Service to implement a Genomic Medicine Service. We conducted a systematic literature review to identify what is known about factors related to the implementation of genomic medicine in routine health care and to draw out the implications for the UK and other settings.

Methods: Relevant studies were identified in Web of Science and PubMed from their date of inception to April 2018.

Germline selection shapes human mitochondrial DNA diversity.

Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.

The importance of clinician, patient and researcher collaborations in Alport syndrome.

Alport syndrome is caused by mutations in the genes COL4A3, COL4A4 or COL4A5 and is characterised by progressive glomerular disease, sensorineural hearing loss and ocular defects. Occurring in less than 1:5000, Alport syndrome is a rare genetic disorder but still accounts for > 1% of the prevalent population receiving renal replacement therapy. There is also increasing awareness about the risk of chronic kidney disease in individuals with heterozygous mutations in Alport syndrome genes.

Correction: Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height.

[This corrects the article DOI: 10.18632/oncotarget.385.

Pathogenicity and selective constraint on variation near splice sites.

Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected parents, as well as more than 60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice sites and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects, and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance.

Assisted reproductive technologies to prevent human mitochondrial disease transmission.

Mitochondria are essential cytoplasmic organelles that generate energy (ATP) by oxidative phosphorylation and mediate key cellular processes such as apoptosis. They are maternally inherited and in humans contain a 16,569-base-pair circular genome (mtDNA) encoding 37 genes required for oxidative phosphorylation. Mutations in mtDNA cause a range of pathologies, commonly affecting energy-demanding tissues such as muscle and brain.

Genetic testing in intellectual disability psychiatry: Opinions and practices of UK child and intellectual disability psychiatrists.

Background: An increasing number of genetic causes of intellectual disabilities (ID) are identifiable by clinical genetic testing, offering the prospect of bespoke patient management. However, little is known about the practices of psychiatrists and their views on genetic testing.

Method: We undertook an online survey of 215 psychiatrists, who were contacted via the Royal College of Psychiatrist's Child and Adolescent and Intellectual Disability Psychiatry mailing lists.

De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome.

Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis.

Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders.

Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is currently unclear. Here we present 19 de novo mutations in this gene, including five missense mutations, identified by the Deciphering Developmental Disorder study. Protein structural analysis reveals that the missense mutations are either close to the ATP or peptide binding-sites within the kinase domain, or are important for protein stability, suggesting they lead to a loss of the protein's function mechanism.