gene, located in Xp11.21, has recently been found to cause XLMR associated with CL/P (12
). The gene is composed of 22 exons with an open-reading frame of 3075 bp. It encodes a protein of 1024 amino acids and contains a plant homeodomain (PHD) zinc finger domain (amino acid positions 7–53) and a JmjC domain (amino acid positions 195–294). It also has six NLS. The PHF8
transcript is ubiquitously expressed with a relatively high expression in the embryonic and early post-natal stages of brain development (12
). The PHF8 protein is a new member of the PHD finger protein family. These proteins function as transcriptional regulators affecting eukaryotic gene expression by chromatin remodeling. The two truncating mutations previously reported in this gene are present either in or after the JmjC domain (12
In this study, we identified a novel de novo nonsense mutation (p.K177X) that results in the premature truncation of the PHF8 protein and the loss of the JmjC domain and five NLS. Unfortunately, because no cell line was available from the patient, it was not possible to determine if the truncating mutation resulted in nonsense-mediated decay of the altered transcript. The clinical phenotype of the proband (CMS12076) consisted of cleft lip, cleft palate, MR and microcephaly.
The observation of this mutation further confirms that PHF8 gene is associated with XLMR with CL/P. It also supports the hypothesis that the PHF8 protein may be involved in the development of cognitive function and midline formation.
The two families with PHF8
mutations reported by Laumonnier et al. (12
) had at least one affected individual, in whom MR without clefting was the clinical finding. One possible explanation for this could be reduced penetrance in these families. Based on this possibility, we decided to screen family MRX81 although the screening of other linked families by Laumonnier et al. (12
) had been negative. Our screening detected no alteration in the PHF8
gene. However, this gene cannot be excluded as causative for this family because only the coding sequence of the gene was screened.
In the present study, 1 of 25 of the male individuals with MR and oral cleft-related phenotypes showed a mutation in the PHF8 gene. Although the yield of mutations identified was relatively low, finding a mutation could be of considerable significance to the families concerned in terms of genetic counseling and the identification of other family members potentially at risk, such as carrier women. Thus, we consider that, based on our findings, men with MR and cleft lip or cleft palate and patients with a family history of XLMR with cleft lip or cleft palate should be considered for screening for mutations in the PHF8 gene.