Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes

Abstract

Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3–5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.

On the association between Chiari malformation type 1, bone mineral density and bone related genes

“…WNT16 locus is one of the most consistent bone-related GWAS signals, and has been associated with different skeletal phenotypes, including BMD, bone strength, geometric parameters, cortical bone thickness and fracture risk (reviewed in Martínez-Gil et al, 2022 ). No variants in WNT16 have been previously associated with C1M, but this pathology has been associated with other members of the Wnt pathway, such as DKK1 , a Wnt pathway inhibitor, in which three missense variants, whose partial loss-of-function has been recently demonstrated by our group ( Martínez-Gil et al, 2020 ), were identified in C1M cases ( Provenzano et al, 2021 ; Merello et al, 2017 ). In addition, Whyte et al (2004) described one HBM woman with gain-of-function variants in LRP5 , a canonical Wnt pathway coreceptor, who also presented with a headache and C1M.…”

“…Nevertheless, this could also be a spurious finding, as it is only one individual. In order to elucidate the relationship between the C1M and bone mass, it would be crucial to measure the LS and FN BMD of the C1M patients from previous publications ( Boyles et al, 2006 ; Markunas et al, 2013 ; Urbizu et al, 2013 ; Markunas et al, 2014 ; Rosenblum et al, 2019 ; Gonçalves et al, 2019 ; Merello et al, 2017 ; Urbizu et al, 2021 ; Provenzano et al, 2021 ; Sadler et al, 2021 ), thus increasing the size of the cohort of patients with C1M and BMD.…”

“…The fact that the cranial bone constriction is suspected to be the most common biologic mechanism leading to C1M suggests that variants in genes related with bone metabolism may be contributing to the malformation through an incorrect development of the cranial bone. This hypothesis is reinforced by the findings of several recent works which have found association of C1M with rare variants in genes involved in collagen metabolism ( Urbizu et al, 2021 ), in Wnt pathway genes ( Merello et al, 2017 ), or in cranial bone sutures ( Provenzano et al, 2021 ).…”

“…The main recent strategy to find the genetic basis of the disease and the inheritance pattern has involved the use of next generation sequencing (NGS) techniques such as whole exome sequencing (WES). These works have found several genes, including chromodomain genes ( Sadler et al, 2021 ) and chromatin remodeling genes ( Provenzano et al, 2021 ).…”

Dissection of contiguous gene effects for deletions around ERF on chromosome 19

“…Disease‐causing heterozygous loss‐of‐function variants of ERF were first described in 2013, in 12 families segregating features of a newly recognized syndrome (termed ERF ‐related craniosynostosis or craniosynostosis type 4, OMIM# 600775), characterized by premature fusion of the cranial sutures (craniosynostosis), hypertelorism, and mild midface hypoplasia (Twigg et al, 2013). Confirmatory case reports have followed (Chaudhry et al, 2015; Korberg et al, 2020; Lee et al, 2018; Provenzano et al, 2021; Timberlake et al, 2017; Tønne et al, 2020; Yoon et al, 2020), and the clinical features of the disorder were further delineated and summarized in 16 additional families by Glass et al (2019). In addition to craniosynostosis and facial dysmorphism, additional frequently associated features included Chiari‐1 malformation, speech and language delay, poor gross and/or fine motor control, hyperactivity, and poor concentration.…”