Korf, Bruce R.

This Perspective discusses whether secondary genomic findings in the clinical context of diagnostic genomic sequencing tests should be sought and reported.

Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals’ family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants.

Background High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD). Methods This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28). Results A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations. Conclusion Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2 -related NDD.

Abstract Purpose: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder associated primarily with bilateral schwannomas seen on the superior vestibular branches of the eighth cranial nerves. Significant morbidity can result from surgical treatment of these tumors. Meningiomas, ependymomas, and other benign central nervous system tumors are also common in NF2. The lack of effective treatments for NF2 marks an unmet medical need. Experimental Design: Here, we provide recommendations from a workshop, cochaired by Drs. D. Gareth Evans and Marco Giovannini, of 36 international researchers, physicians, representatives of the biotechnology industry, and patient advocates on how to accelerate progress toward NF2 clinical trials. Results: Workshop participants reached a consensus that, based on current knowledge, the time is right to plan and implement NF2 clinical trials. Obstacles impeding NF2 clinical trials and how to address them were discussed, as well as the candidate therapeutic pipeline for NF2. Conclusions: Both phase 0 and phase II NF2 trials are near-term options for NF2 clinical trials. The number of NF2 patients in the population remains limited, and successful recruitment will require ongoing collaboration efforts between NF2 clinics. (Clin Cancer Res 2009;15(16):5032–9)