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.
Highlights
Primary or congenital malformations of Chiari are structural defects in the brain and spinal cord that occur during fetal development and range from cerebellar tonsillar herniation through the foramen magnum to the absence of the cerebellum1 3 Vol.:(0123456789)Human Genetics (2021) 140:625–647 with or without other associated intracranial or extracranial defects such as hydrocephalus, syrinx, encephalocele or spinal dysraphism
According to the Whole-exome sequencing (WES) results, patients were divided into four categories (a–d): (i) affected by a syndrome in which common type 1 malformation (C1M) was already reported at least in some cases (a); (ii) affected by a syndrome in which C1M was never reported (b); (iii) affected by isolated C1M (c); and (iv) without any obvious disease-variant (d)
This study shows that C1M, both syndromic and isolated, is mainly dependent on variants in chromatin-remodeling genes, in most cases of the missense type and in very few cases presumably leading to a truncated protein (PTV protein truncation variant)
Summary
Primary or congenital malformations of Chiari are structural defects in the brain and spinal cord that occur during fetal development and range from cerebellar tonsillar herniation through the foramen magnum to the absence of the cerebellum1 3 Vol.:(0123456789)Human Genetics (2021) 140:625–647 with or without other associated intracranial or extracranial defects such as hydrocephalus, syrinx, encephalocele or spinal dysraphism. Primary or congenital malformations of Chiari are structural defects in the brain and spinal cord that occur during fetal development and range from cerebellar tonsillar herniation through the foramen magnum to the absence of the cerebellum. The signs of C1M can appear in adulthood or before adolescence, in the latter case with about 40% of subjects are under the age of 5 years, 25% of 5–10 years and 30% of 10–15 years (Tubbs 2007; McVige 2014; Piper 2019). The most common symptoms are occipital or upper cervical headaches, exacerbated by valsalva maneuver (tension, coughing, and sneezing) (McVige 2014; Piper 2019). Syringomyelia is present in 60–70% of patients, with progressive scoliosis in 30% of cases (Poretti 2016)
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