DDX3X, WDR45 and the ongoing mystery of X-linked disorders

X-linked. Almost a decade ago, the former EuroEPINOMICS team was asked to perform a difficult task. We reviewed inherited variants in X-linked genes, trying to understand whether inherited variants are causative of neurodevelopmental disorders for one of our research studies. In most cases, we decided that we did not have enough evidence. How could we tell whether variants in genes such as HUWE1 or CNKSR2 that were transmitted from unaffected females to affected sons were disease-causing or not? I remembered my frustration when I came across a publication on the contribution of X-linked variants to neurodevelopmental disorders that was published last year. Continue reading

The IQSEC2 mystery – exploring the phenotype of an X-linked disease in males and females

The X-factor. Interpreting variants in X chromosome genes in a clinical context is an ongoing diagnostic challenge, regardless of whether the variant is identified in a male or female patient. The majority of X-linked conditions affect hemizygous male individuals, with heterozygous carrier girls and women largely unaffected or much less severely affected. PCDH19-Epilepsy is, of course, a notable rule breaker in this regard. However, we are learning that other X-linked conditions don’t play by the traditional rules either, and affected heterozygous females are being described for some other X-linked conditions. In some cases, including SMC1A– and NEXMIF– (formerly called KIAA2022) related disorders, the phenotypes in males versus females are more or less distinct. However, in other X-linked conditions, including IQSEC2-encephalopathy, both affected males and females share a continuum of similar features. A recent publication in Genetics in Medicine explores and expands the spectrum of IQSEC2-encephalopathy and delves into what is similar – and what is distinct – in affected male and female patients. Continue reading

The novel gene dilemma

N-of-1. The use of whole exome sequencing has led to many of the recent genes discovered in the epilepsy field. However, in contrast to established genes or emerging genes that are found in several patients, there is a significant proportion of patients who carry de novo mutations in novel genes. In many cases, these novel genes look very suspicious. One aspect of a recent publication in Genetics in Medicine was to assess how these suspicious candidates convert to established genes over time. Continue reading