14q32.11 microdeletion including CALM1, TTC7B, PSMC1, and RPS6KA5:A new potential cause of developmental and language delay in three unrelated patients

Three unrelated patients with similar microdeletions of chromosome 14q32.11 with shared phenotypes including language and developmental delay, and four overlapping genes -CALM1, TTC7B, PSMC1, and RPS6KA5 have been presented. All four genes are expressed in the brain and have haploinsufficiency scores, which reflect low tolerance to loss of function variation. An insight on the genes in the overlapping region, which may influence the resulting phenotype has been provided. Given the three patients' similar phenotypes and lack of normal variation in this region, it was suggested that this microdeletion may be associated with developmental and language delay.</p

Accumulating mutations in series of haplotypes at the KIT and MITF loci are major determinants of white markings in Franches-Montagnes horses.

Coat color and pattern variations in domestic animals are frequently inherited as simple monogenic traits, but a number are known to have a complex genetic basis. While the analysis of complex trait data remains a challenge in all species, we can use the reduced haplotypic diversity in domestic animal populations to gain insight into the genomic interactions underlying complex phenotypes. White face and leg markings are examples of complex traits in horses where little is known of the underlying genetics. In this study, Franches-Montagnes (FM) horses were scored for the occurrence of white facial and leg markings using a standardized scoring system. A genome-wide association study (GWAS) was performed for several white patterning traits in 1,077 FM horses. Seven quantitative trait loci (QTL) affecting the white marking score with p-values p≤10(-4) were identified. Three loci, MC1R and the known white spotting genes, KIT and MITF, were identified as the major loci underlying the extent of white patterning in this breed. Together, the seven loci explain 54% of the genetic variance in total white marking score, while MITF and KIT alone account for 26%. Although MITF and KIT are the major loci controlling white patterning, their influence varies according to the basic coat color of the horse and the specific body location of the white patterning. Fine mapping across the MITF and KIT loci was used to characterize haplotypes present. Phylogenetic relationships among haplotypes were calculated to assess their selective and evolutionary influences on the extent of white patterning. This novel approach shows that KIT and MITF act in an additive manner and that accumulating mutations at these loci progressively increase the extent of white markings

Protocol for finding genetic variation associated with unmeasured traits through GenomicSEM common-factor GWAS

Summary: Here, we present a protocol for finding genetic variation associated with unmeasured traits using common-factor genome-wide association study (GWAS) using genomic structural equation modeling (GenomicSEM), applied here to nociplastic pain. We use existing GWAS for six chronic overlapping pain condition traits. We describe steps for preparing the computing environment and packages, identifying relevant GWAS and retrieving summary statistics, preparing summary statistics for multivariable Linkage Disequilibrium-score regression, and running common-factor GWAS using GenomicSEM without and with individual single-nucleotide polymorphism (SNP) effects.For complete details on the use and execution of this protocol, please refer to Johnston et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics

Mutations in STAG2 cause an X-linked cohesinopathy associated with undergrowth, developmental delay, and dysmorphia: Expanding the phenotype in males.

BACKGROUND: The cohesin complex is a multi-subunit protein complex which regulates sister chromatid cohesion and separation during cellular division. In addition, this evolutionarily conserved protein complex plays an integral role in DNA replication, DNA repair, and the regulation of transcription. The core complex is composed of four subunits: RAD21, SMC1A, SMC3, and STAG1/2. Mutations in these proteins have been implicated in human developmental disorders collectively termed cohesinopathies. METHODS: Using clinical exome sequencing, we have previously identified three female cases with heterozygous STAG2 mutations and overlapping syndromic phenotypes. Subsequently, a familial missense variant was identified in five male family members. RESULTS: We now present the case of a 4-year-old male with developmental delay, failure to thrive, short stature, and polydactyly with a likely pathogenic STAG2 de novo missense hemizygous variant, c.3027A&gt;T, p.Lys1009Asn. Furthermore, we compare the phenotypes of the four previously reported STAG2 variants with our case. CONCLUSION: We conclude that mutations in STAG2 cause a novel constellation of sex-specific cohesinopathy-related phenotypes and are furthermore, essential for neurodevelopment, human growth, and behavioral development

What next for eating disorder genetics? Replacing myths with facts to sharpen our understanding

AbstractSubstantial progress has been made in the understanding of anorexia nervosa (AN) and eating disorder (ED) genetics through the efforts of large-scale collaborative consortia, yielding the first genome-wide significant loci, AN-associated genes, and insights into metabo-psychiatric underpinnings of the disorders. However, the translatability, generalizability, and reach of these insights are hampered by an overly narrow focus in our research. In particular, stereotypes, myths, assumptions and misconceptions have resulted in incomplete or incorrect understandings of ED presentations and trajectories, and exclusion of certain patient groups from our studies. In this review, we aim to counteract these historical imbalances. Taking as our starting point the Academy for Eating Disorders (AED) Truth #5 “Eating disorders affect people of all genders, ages, races, ethnicities, body shapes and weights, sexual orientations, and socioeconomic statuses”, we discuss what we do and do not know about the genetic underpinnings of EDs among people in each of these groups, and suggest strategies to design more inclusive studies. In the second half of our review, we outline broad strategic goals whereby ED researchers can expand the diversity, insights, and clinical translatability of their studies.</jats:p

Recurrent respiratory viral diseases and chronic sequelae due to dominant negative IFIH1

Viral respiratory infections are the most common childhood infection worldwide. However, even common pathogens can have significant consequences in the context of patients with primary immunodeficiency diseases. More than half or viral infections annually are due to rhinovirus/enterovirus strains. Most clinical manifestations of viral infection are mild. However 3% of cases result in hospitalization in patients who have no other known risk factors. These patients may have an inborn error of immunity, a genetic susceptibility to viral infections. Here we present the case of an adult male who suffered respiratory viral infections his whole life and developed chronic, inflammatory damage to sinuses and lungs as a consequence. Genomic sequencing identified compound heterozygous variants in the IFIH1 gene, encoding the protein Melanoma Differentiation Association Protein 5 (MDA5), a RIG-I-like cytoplasmic sensor of RNA intracellular infections. We show a dominant negative effect on these variants on the level of interferon-induced expression of MDA5 protein. This work supports that loss-of-function variants in IFIH1 affect the sensing of viral infections. Underlying genomic variants may dictate the point at which recurrent, respiratory viral infections leave commonplace experience and incur lasting damage.</jats:p

Myopathy associated with homozygous PYROXD1

Biallelic pathogenic variants in the gene PYROXD1 have recently been described to cause early-onset autosomal recessive myopathy. Myopathy associated with PYROXD1 pathogenic variants is rare and reported in only 17 individuals. Known pathogenic variants in PYROXD1 include missense, insertion and essential splice-site variants. Here we describe a consanguineous family of individuals affected with late-onset myopathy and homozygous PYROXD1 missense variants (NM_024854.5:c.464A&gt;G [p.Asn155Ser]) expanding our understanding of the possible disease phenotypes of PYROXD1-associated myopathy

Non-cancer-related pathogenic germline variants and expression consequences in ten-thousand cancer genomes

Abstract Background DNA sequencing is increasingly incorporated into the routine care of cancer patients, many of whom also carry inherited, moderate/high-penetrance variants associated with other diseases. Yet, the prevalence and consequence of such variants remain unclear. Methods We analyzed the germline genomes of 10,389 adult cancer cases in the TCGA cohort, identifying pathogenic/likely pathogenic variants in autosomal-dominant genes, autosomal-recessive genes, and 59 medically actionable genes curated by the American College of Molecular Genetics (i.e., the ACMG 59 genes). We also analyzed variant- and gene-level expression consequences in carriers. Results The affected genes exhibited varying pan-ancestry and population-specific patterns, and overall, the European population showed the highest frequency of pathogenic/likely pathogenic variants. We further identified genes showing expression consequence supporting variant functionality, including altered gene expression, allelic specific expression, and mis-splicing determined by a massively parallel splicing assay. Conclusions Our results demonstrate that expression-altering variants are found in a substantial fraction of cases and illustrate the yield of genomic risk assessments for a wide range of diseases across diverse populations. </jats:sec

Non-cancer-related pathogenic germline variants and expression consequences in ten-thousand cancer genomes

Background DNA sequencing is increasingly incorporated into the routine care of cancer patients, many of whom also carry inherited, moderate/high-penetrance variants associated with other diseases. Yet, the prevalence and consequence of such variants remain unclear. Methods We analyzed the germline genomes of 10,389 adult cancer cases in the TCGA cohort, identifying pathogenic/likely pathogenic variants in autosomal-dominant genes, autosomal-recessive genes, and 59 medically actionable genes curated by the American College of Molecular Genetics (i.e., the ACMG 59 genes). We also analyzed variant- and gene-level expression consequences in carriers. Results The affected genes exhibited varying pan-ancestry and population-specific patterns, and overall, the European population showed the highest frequency of pathogenic/likely pathogenic variants. We further identified genes showing expression consequence supporting variant functionality, including altered gene expression, allelic specific expression, and mis-splicing determined by a massively parallel splicing assay. Conclusions Our results demonstrate that expression-altering variants are found in a substantial fraction of cases and illustrate the yield of genomic risk assessments for a wide range of diseases across diverse populations