Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Abstract

The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article.

Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome

“…We performed Human Phenotype Ontology (HPO)-based clustering analysis using 35 individuals with de novo CHD3 variants, 6 20 of 21 probands with an inherited CHD3 variant, and 20 of 21 heterozygote parents in the analysis; the proband and heterozygote mother of family 6 were excluded because no clinical data were available and the mother was mosaic for the CHD3 variant (approximately 37%). The Wang score (a measure of semantic similarity) between all terms was calculated using the HPO Sim package.…”

“…The cloning of CHD3 (NM_001005273.2/ENST0000033 0494.7) has been described previously. 6 The coding DNA sequence of GATAD2B (NM_020699.3/ENST00000368 655.4) and a C-terminal region of CHD3-encoding residues 1246 to 1944 (NM_001005273.2) were amplified using primers listed in Supplemental Table 2. Variants in fulllength CHD3 or the C-terminal CHD3 construct were generated using the QuikChange Lightning Site-Directed Mutagenesis Kit (Agilent).…”

“…CHD3 is an adenosine triphosphate-dependent chromatin remodeling protein that serves as a core member of the Nucleosome Remodeling Deacetylase complex. 6 Heterozygous variants in CHD3 have recently been shown to cause a neurodevelopmental syndrome with a variable phenotype, ranging from mildly to more severely affected cases (Snijders Blok-Campeau syndrome [SNIBCPS], OMIM #618205). 6,7 CHD3 is extremely intolerant for both loss-of-function (LoF) and missense variation (probability of LoF intolerance = 1, observed/expected = 0.09 [0.05-0.15]; Z = 6.15, observed/expected = 0.5 [0.46-0.53]), suggesting haploinsufficiency as a possible disease mechanism.…”

“…6 Heterozygous variants in CHD3 have recently been shown to cause a neurodevelopmental syndrome with a variable phenotype, ranging from mildly to more severely affected cases (Snijders Blok-Campeau syndrome [SNIBCPS], OMIM #618205). 6,7 CHD3 is extremely intolerant for both loss-of-function (LoF) and missense variation (probability of LoF intolerance = 1, observed/expected = 0.09 [0.05-0.15]; Z = 6.15, observed/expected = 0.5 [0.46-0.53]), suggesting haploinsufficiency as a possible disease mechanism. However, the large majority of cases diagnosed with SNIBCPS carry confirmed de novo missense variants or single amino acid in-frame deletion variants (51/55, 93% of cases), 6,7 clustering in the adenosine triphosphatase (ATPase)-helicase domain of the encoded protein and affecting its ATPase activity and/or chromatin remodeling functions, which could be consistent with a dominantnegative mechanism.…”

“…6,7 CHD3 is extremely intolerant for both loss-of-function (LoF) and missense variation (probability of LoF intolerance = 1, observed/expected = 0.09 [0.05-0.15]; Z = 6.15, observed/expected = 0.5 [0.46-0.53]), suggesting haploinsufficiency as a possible disease mechanism. However, the large majority of cases diagnosed with SNIBCPS carry confirmed de novo missense variants or single amino acid in-frame deletion variants (51/55, 93% of cases), 6,7 clustering in the adenosine triphosphatase (ATPase)-helicase domain of the encoded protein and affecting its ATPase activity and/or chromatin remodeling functions, which could be consistent with a dominantnegative mechanism. 6 We assembled a cohort of 21 families with inherited CHD3 variants and used a combination of objectified indepth clinical analyses, cell-based expression studies, and large population cohort analyses to confirm the association of inherited CHD3 variants with SNIBCPS and to show that heterozygote parents, who were predominantly females, often have (very) mild phenotypes, showing variable expressivity.…”