De novo chromatin remodelling variants in sporadic Chiari 1 malformation.

Large-effect de novo variants in CHD1, CHD3, CHD4 and CHD8, clustering within ATPase, helicase and chromodomain regions, disrupting chromatin-remodelling programs of the developing cerebellum.

Chiari 1 malformation is the most common congenital malformation of the human hindbrain, and although chromatin-remodelling genes had already been implicated, the de novo genetic architecture remained poorly defined. The authors performed exome sequencing in an ultra-rare multigenerational family combining Chiari 1, syringomyelia and tethered cord, then in the largest trio-based cohort assembled to date, 1,585 proband-parent trios with sporadic idiopathic Chiari 1 (2017-2025), compared with 1,798 unaffected control siblings. A heterozygous loss-of-function CHD3 variant segregated with the malformation and syringomyelia in the family, and in the trio cohort rare protein-altering de novo variants were significantly enriched across several CHD genes including CHD1, CHD3, CHD4 and CHD8 (protein-damaging variants P = 1.3 × 10⁻⁹; predicted loss-of-function variants P = 8.6 × 10⁻⁵), with two pathogenic variants in CHD1 and three new variants each in CHD4 and CHD8. Variants clustered within conserved ATPase, helicase and chromodomain regions, these patients frequently had comorbid developmental delay and related neurodevelopmental features, and single-cell transcriptomic data showed enrichment in Purkinje cells and inhibitory neurons of the midgestational cerebellum.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

One thousand five hundred and eighty-five trios with control siblings is the scale that was missing to move Chiari 1 malformation beyond a purely anatomical and neurosurgical framing. The practical consequence is contained in one sentence from the authors: when sporadic Chiari 1 occurs in a child who also has neurodevelopmental features, exome sequencing provides prognostic and counselling information that imaging does not. It should be kept in mind, however, that CHD4 and CHD8 are already well-established neurodevelopmental disorder genes: the open question is whether the malformation is one further feature of those syndromes or an entity of its own.

Analysis by Dr Thibaut Benquey