Explore the vast range of titles available.

Increasing numbers of genes are being implicated in Mendelian disorders and incorporated into clinical test panels. However, lack of evidence supporting the gene-disease relationship can hinder interpretation. We explored the utility of testing 51 additional genes for hypertrophic cardiomyopathy (HCM), one of the most commonly tested Mendelian disorders. Using genome sequencing data from 240 sarcomere gene negative HCM cases and 6229 controls, we undertook case-control and individual variant analyses to assess 51 genes that have been proposed for HCM testing. We found no evidence to suggest that rare variants in these genes are prevalent causes of HCM. One variant, in a single case, was categorized as likely to be pathogenic. Over 99% of variants were classified as a variant of uncertain significance (VUS) and 54% of cases had one or more VUS. For almost all genes, the gene-disease relationship could not be validated and lack of evidence precluded variant interpretation. Thus, the incremental diagnostic yield of extending testing was negligible, and would, we propose, be outweighed by problems that arise with a high rate of uninterpretable findings. These findings highlight the need for rigorous, evidence-based selection of genes for clinical test panels.

According to best practice guidelines, any such variant detected in an affected individual can be assumed to be causative.1 Does this mean that all DMD deletions and duplications can be assumed to be disease causing? Table 1 Phenotypic details of select individuals from each of the six families in which DMD_E42_Dup was detected Family Proband or relative Sex Age at referral* Dystrophinopathy suspected? CK Phenotypic/other notes 1 Relative M L40s No 176 No muscular weakness, active lifestyle including regular gym attendance. 2 Proband M E10s No – Speech and language delay, autism. 3 Proband M L10s No 250 Global developmental delay. [...]heterozygous for a sarcomere gene variant of uncertain significance. *Approximate age as decade of life at referral: E, early; L, late. [...]with respect to D/BMD, we suggest that this variant can be clinically classified as likely benign, based on American College of Medical Genetics and Genomics (ACMG) codes BS1 (allele frequency is greater than expected for disorder), BS2 (observed in healthy adult males for an X linked disorder with full penetrance expected at an early age) and arguably PM4 (protein length changes due to in-frame insertions in a non-repeat region).7 8 Although we cannot exclude that this variant may predispose to muscular problems or DCM in old age, we believe this is unlikely given the absence of relevant family history in our families.

In recent years, molecular genetics research has identified a large number of putative susceptibility genes for a variety of complex psychiatric and neurodegenerative disorders. However, in most instances, the particular functional variants involved have not been identified, and it is typically unclear by what mechanism the pathogenic effect is mediated. Where a genetic association does not appear to be fully explicable by variants that alter the amino acid sequence of a protein, it is a reasonable hypothesis that the association might be mediated by cis-acting variants that alter gene expression. This hypothesis was tested in this thesis in relation to 10 putative susceptibility genes for psychiatric and neurodegenerative disorders. The genes were DISCI, RELN, GABRA4, GABRA5, GABRB1, GABRB2, GABRG2, GABRG3, NOS1AP and MAPT. Each one of these genes was investigated by assays of relative allelic expression applied to a large number of post mortem human brain samples. Samples were also genotyped for relevant variants that had previously shown association with disease in order to test those variants for a putative cis-regulatory effect. Cis-regulatory variation manifested as unequal expression of each parental gene copy at the mRNA level was detected in nearly all of the genes in at least one tissue sample. However, for only two genes (RELN and MAPT) was evidence obtained that specific variants implicated in disease influenced expression.