Exome Sequencing Fails to Identify the Genetic Cause of Aicardi Syndrome

Abstract

Aicardi syndrome (AS) is a well-characterized neurodevelopmental disorder with an unknown etiology. In this study, we performed whole-exome sequencing in 11 female patients with the diagnosis of AS, in order to identify the disease-causing gene. In particular, we focused on detecting variants in the X chromosome, including the analysis of variants with a low number of sequencing reads, in case of somatic mosaicism. For 2 of the patients, we also sequenced the exome of the parents to search for de novo mutations. We did not identify any genetic variants likely to be damaging. Only one single missense variant was identified by the de novo analyses of the 2 trios, and this was considered benign. The failure to identify a disease gene in this study may be due to technical limitations of our study design, including the possibility that the genetic aberration leading to AS is situated in a non-exonic region or that the mutation is somatic and not detectable by our approach. Alternatively, it is possible that AS is genetically heterogeneous and that 11 patients are not sufficient to reveal the causative genes. Future studies of AS should consider designs where also non-exonic regions are explored and apply a sequencing depth so that also low-grade somatic mosaicism can be detected.

Advanced genomic testing may aid in counseling of isolated agenesis of the corpus callosum on prenatal ultrasound

“…Furthermore, such a panel should be updated regularly when new ACC-related genes are discovered.Yet, although NGS could be very valuable in fetuses with isolated cACC, it will, at present, not be able to identify all important cACC syndromes. This is illustrated by Aicardi syndrome (case 17), a clinically distinct entity which is genetically still unraveled 30,36. 5 | CONCLUSIONIn accordance with current guidelines, we conclude that microarray should be offered in case of isolated cACC on ultrasound.…”

“…Yet, although NGS could be very valuable in fetuses with isolated cACC, it will, at present, not be able to identify all important cACC syndromes. This is illustrated by Aicardi syndrome (case 17), a clinically distinct entity which is genetically still unraveled …”

Aicardi syndrome, an unsolved mystery: Review of diagnostic features, previous attempts, and future opportunities for genetic examination

“…The most recently published genetic studies of AIC are now utilizing next‐generation sequencing technologies for generation and analyses of genomic and transcriptomic level data. A limited number of individuals with AIC have undergone sequencing and subsequent analyses (i.e., whole‐exome sequencing [WES], whole‐genome sequencing [WGS], RNA‐sequencing [RNA‐seq], and methylation array) (Lund et al, ; Piras et al, ; Schrauwen et al, ). Overall, the data generated from these limited sample numbers have not yielded any definitive etiology of AIC.…”

3D facial morphometry in Italian patients affected by Aicardi syndrome

“…Extensive genetic studies carried on so far by several international research groups, such as skewed X‐inactivation analysis (Eble et al, 2009), candidate genes studies (Van den Veyver et al, 2004), methylation array (Piras et al, 2017), exome, and genome sequencing (Lund et al, 2016; Wang et al, 2009; Wong & Sutton, 2018), failed to solve the AIC etiology. Considering the absence of a genetic etiology, AIC diagnosis is still a challenge because diagnostic criteria are based only on clinical and radiological features (Aicardi, 2005; Sutton et al, 2005).…”