Concurrent de novo ZFHX4 variant and 16q24.1 deletion in a patient with orofacial clefting; a potential role of ZFHX4 and USP10

Abstract

A girl with a unilateral cleft lip, alveolus and palate, tooth agenesis, and mild dysmorphic features, without a specific underlying syndrome diagnosis, was genotypically characterized and phenotypically described. Cleft gene panel analysis, single‐nucleotide polymorphism (SNP) array, whole genome sequencing (WGS), whole exome sequencing, and quantitative PCR (Q‐PCR) analysis were used as diagnostic tests. SNP array revealed a maternal deletion at 16q24.1, encompassing the cleft candidate gene USP10. WES revealed an additional de novo Loss‐of‐Function variant (p.(Asn838fs)) in the Zinc‐Finger‐Homeobox‐4 (ZFHX4) gene. Q‐PCR was performed to explore the effect of the ZFHX4 variant and the deletion in 16q24.1. The mRNA expression of a selection of putative target genes involved in orofacial clefting showed a lowered expression of USP10 (52%), CRISPLD2 (31%), and CRISPLD1 (1%) compared to the control. IRF6 showed no difference in gene expression. This case supports ZFHX4 as a novel cleft gene and suggests USP10 may contribute to the etiology of orofacial clefts in humans.

Diagnostic Gene Panel Testing in (Non)-Syndromic Patients with Cleft Lip, Alveolus and/or Palate in the Netherlands

“…Interestingly, in a girl with a unilateral CLA/P, WES revealed a de novo pathogenic variant in the novel cleft gene ZFHX4 concurrently with a 16q24.1 deletion, encompassing the gene USP10. This case is reported as a separate case report, supporting ZFHX4 as a novel cleft gene and demonstrating co-occurrence of a pathogenic gene variant and a chromosome deletion, and may contribute to the etiology of orofacial cleft (Créton. 2023).…”

“…In one of these cases, a pathogenic variant in the novel cleft gene ZFHX4 gene with a concurrent deletion 16q24.1 deletion, encompassing the gene USP10, was identified. This case is recently reported as a separate case report [Créton et al, 2023]. Inclusion of the results of the reported additional tests would increase the total yield of confirmed diagnoses in this cohort to 32 of 212 cases (15.1%).…”

Shifting the Focus of Molecular Syndromology from Individual Diagnoses to Outcome Analyses

“…Thus, in 8 out of 212 patients (3.8%), a clinically relevant CNV or SNV was uncovered. In 1 patient with a unilateral CLA/P a de novo pathogenic variant in ZFHX4, concomitant with a deletion in the 16q24.1 region was revealed by WES [Créton et al, 2023]. Hence, ZFHX4 is likely a novel gene for a recessive form of CLA/P.…”