PARD3gene variation as candidate cause of nonsyndromic cleft palate only

Abstract

Nonsyndromic cleft palate only (NSCP) is a common congenital malformation worldwide. In this study, we report a three‐generation pedigree with NSCP following the autosomal‐dominant pattern. Whole‐exome sequencing and Sanger sequencing revealed that only the frameshift variant c.1012dupG [p. E338Gfs*26] in PARD3 cosegregated with the disease. In zebrafish embryos, ethmoid plate patterning defects were observed with PARD3 ortholog disruption or expression of patient‐derived N‐terminal truncating PARD3 (c.1012dupG), which implicated PARD3 in ethmoid plate morphogenesis. PARD3 plays vital roles in determining cellular polarity. Compared with the apical distribution of wild‐type PARD3, PARD3‐p. E338Gfs*26 mainly localized to the basal membrane in 3D‐cultured MCF‐10A epithelial cells. The interaction between PARD3‐p. E338Gfs*26 and endogenous PARD3 was identified by LC–MS/MS and validated by co‐IP. Immunofluorescence analysis showed that PARD3‐p. E338Gfs*26 substantially altered the localization of endogenous PARD3 to the basement membrane in 3D‐cultured MCF‐10A cells. Furthermore, seven variants, including one nonsense variant and six missense variants, were identified in the coding region of PARD3 in sporadic cases with NSCP. Subsequent analysis showed that PARD3‐p. R133*, like the insertion variant of c.1012dupG, also changed the localization of endogenous full‐length PARD3 and that its expression induced abnormal ethmoid plate morphogenesis in zebrafish. Based on these data, we reveal PARD3 gene variation as a novel candidate cause of nonsyndromic cleft palate only.

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

“…Regarding rare sequence-level variants, a heterozygous frameshift variant, NM_019619.4(PARD3): c.1012dupG (p.Glu338GlyfsTer26), was identified in six patients from a Chinese family manifesting nonsyndromic isolated cleft palate. Ethmoid plate patterning defects observed in zebrafish supported the gene’s candidacy (Cui et al 2022 ).…”

“…S3). Pathogenic variants in CHD3 show variable expressivity in Snijders Blok–Campeau syndrome (OMIM 618205), while PARD3 was associated before with neural tube defects, cleft lip, cleft palate, ASD, and bilateral adrenal hypoplasia (Chen et al 2013 ; Cui et al 2022 ; Özaslan et al 2021 ; van der Spek et al 2022 ). The variant in CHD3 was a predicted splice-site variant, and we did not functionally validate its effect.…”

Read-depth based approach on whole genome resequencing data reveals important insights into the copy number variation (CNV) map of major global buffalo breeds

“…Finally, in Pandharpuri, the greatest CNVR spanned 0.729 Mb of buffalo genome with genomic coordinates spreading across chromosome 2. PARD3 gene was identified in one of the top CNVRs, which is involved in cell growth and division as well as the formation of tight junctions in epithelial cells [ 64 ].…”

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

“…WES identi ed the de novo variant NM_014974.3 (DIP2C): Chinese family manifesting nonsyndromic isolated cleft palate. Ethmoid plate patterning defects observed in zebra sh supported the gene's candidacy(Cui et al, 2022).ZBTB38 is a ubiquitously expressed ZNF transcription factor that belongs to the POZ/BTB family(Costoya, 2007;Sasai et al, 2005). In mice, heterozygous loss of ZBTB38 decreased the expression of Nanog and Sox2 and led to embryonic developmental failure and early embryonic lethality(Nishio et al, 2022).…”