A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome

Abstract

There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 ( CHD3 ), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.

Pathogenic variants inSMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features

“…In general, this novel SMARCA5 -associated syndrome reported here appears to result in a less severe phenotype when compared to other neurodevelopmental disorders due to pathogenic variants in ARID, SMARC , and CHD gene families, where almost all of the variants occur de novo and parent-child transmission is rarely documented ( 49, 55 ). We present here a three-generation pedigree (for individuals 4-6) segregating a deleterious missense variant.…”

“…We identified six missense variants, one splice-altering variant that lead to exon skipping and in-frame deletion, and one recurrent in-frame deletion in eleven individuals from nine unrelated families from around the world. The individuals in our study demonstrated a broad range of clinical features, as is not uncommon in neurodevelopmental disorders associated with pathogenic variants in aforementioned chromatin remodeling complexes (i.e., SWI/SNF, CHD, and ISWI) that vary from isolated autism to syndromic intellectual disability ( 5, 17, 48, 49 ). The most consistent clinical findings in our cohort are postnatal microcephaly and short stature observed in 10/12 individuals, and developmental delay in 8/10 individuals, although again, the severity of these delays varies widely from mild to severe (individual 7).…”

“…Varying degrees of developmental delay have been consistently reported in neurodevelopmental disorders associated with pathogenic variants involved in chromatin remodeling complexes. Similarly, varying head size ranging from microcephalic to macrocephalic is also frequently observed, for example, in SMARCB1 and CHD3 ( 49, 50 ). It is widely acknowledged that different variants within different functional domains of a gene can cause different phenotypes.…”

Pathogenic variants in SMARCA5 , a chromatin remodeler, cause a range of syndromic neurodevelopmental features

“…We identified seven missense variants, one splice-altering variant that led to exon skipping and in-frame deletion, and one recurrent in-frame deletion in 12 individuals from 10 unrelated families from around the world. The individuals in our study demonstrated a broad range of clinical features, as is not uncommon in neurodevelopmental disorders associated with pathogenic variants in aforementioned chromatin remodeling complexes (i.e., SWI/SNF, CHD, and ISWI) that vary from isolated autism to syndromic intellectual disability (5,17,49,50). The most consistent clinical findings in our cohort are postnatal microcephaly and short stature observed in 10 of 12 individuals as well as developmental delay in 8 of 10 individuals, although, again, the severity of these delays varies widely from mild to severe (individual 7).…”

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

“…2 ) [ 208 ]. Patients with CHD3 mutations are only very recently identified with Snijders Blok–Campeau syndrome, which is characterized by ID (with a wide range of severity), developmental delays, macrocephaly, impaired speech and language skills, and characteristic facial features [ 209 , 210 ].…”