Targeted resequencing identifies genes with recurrent variation in cerebral palsy

A growing body of evidence points to a considerable and heterogeneous genetic aetiology of cerebral palsy (CP). To identify recurrently variant CP genes, we designed a custom gene panel of 112 candidate genes. We tested 366 clinically unselected singleton cases with CP, including 271 cases not previously examined using next-generation sequencing technologies. Overall, 5.2% of the naïve cases (14/271) harboured a genetic variant of clinical significance in a known disease gene, with a further 4.8% of individuals (13/271) having a variant in a candidate gene classified as intolerant to variation. In the aggregate cohort of individuals from this study and our previous genomic investigations, six recurrently hit genes contributed at least 4% of disease burden to CP: COL4A1, TUBA1A, AGAP1, L1CAM, MAOB and KIF1A. Significance of Rare VAriants (SORVA) burden analysis identified four genes with a genome-wide significant burden of variants, AGAP1, ERLIN1, ZDHHC9 and PROC, of which we functionally assessed AGAP1 using a zebrafish model. Our investigations reinforce that CP is a heterogeneous neurodevelopmental disorder with known as well as novel genetic determinants.C. L. van Eyk, M. A. Corbett, M. S. B. Frank, D. L. Webber, M. Newman, J. G. Berry, K. Harper, B. P. Haines, G. McMichael, J. A. Woenig, A. H. MacLennan, and J. Gec

Definition and diagnosis of cerebral palsy in genetic studies: a systematic review

Aim: To conduct a systematic review of phenotypic definition and case ascertainment in published genetic studies of cerebral palsy (CP) to inform guidelines for the reporting of such studies. Method: Inclusion criteria comprised genetic studies of candidate genes, with CP as the outcome, published between 1990 and 2019 in the PubMed, Embase, and BIOSIS Citation Index databases. Results: Fifty‐seven studies met the inclusion criteria. We appraised how CP was defined, the quality of information on case ascertainment, and compliance with international consensus guidelines. Seven studies (12%) were poorly described, 33 studies (58%) gave incomplete information, and 17 studies (30%) were well described. Missing key information precluded determining how many studies complied with the definition by Rosenbaum et al. Only 18 out of 57 studies (32%) were compliant with the Surveillance of Cerebral Palsy in Europe (SCPE) international guidelines on defining CP. Interpretation: Limited compliance with international consensus guidelines on phenotypic definition and mediocre reporting of CP case ascertainment hinders the comparison of results among genetic studies of CP (including meta‐analyses), thereby limiting the quality, interpretability, and generalizability of study findings. Compliance with the SCPE guidelines is important for ongoing gene discovery efforts in CP, given the potential for misclassification of unrelated neurological conditions as CP.Ryan Pham, Ben W Mol, Jozef Gecz, Alastair H Maclennan, Suzanna C Maclennan, Mark A Corbett, Clare L Van Eyk, Dani L Webber, Lyle J Palmer, Jesia G Berr

Effectiveness and safety of the oxytocin antagonist atosiban versus beta-adrenergic agonists in the treatment of preterm labour

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Cerebral palsy and genomics: an international consortium

Letter to the edito

Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy

Contains fulltext : 154458.pdf (publisher's version ) (Closed access)Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61 de novo protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks-the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten de novo mutations in three previously identified disease genes (TUBA1A (n=2), SCN8A (n=1) and KDM5C (n=1)) and in six novel candidate CP genes (AGAP1, JHDM1D, MAST1, NAA35, RFX2 and WIPI2) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes, L1CAM and PAK3, and in two novel candidate CP genes, CD99L2 and TENM1. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes