Abstract QS43: Blepharophimosis Ptosis Epicanthus Inversus Syndrome Caused by a ZC3H13 Gene Mutation

Abstract

PURPOSE: Blepharophimosis Ptosis Epicanthus Inversus Syndrome (BPES) is a rare craniofacial autosomal dominant disorder characterized by severe bilateral ptosis, telecanthus, epicanthus inverses, belpharophimosis and orbital dysmorphology. BPES type 1 is accompanied by ovarian failure and attendant infertility, while type 2 manifests only eyelid and orbital involvement. While BPES is often associated with a dominantly inherited mutation in the forkhead transcription factor FOXL2 (3q23), we sought to capitalize on next generation whole exome sequencing to decipher the cause of BPES in a pedigree lacking a FOXL2 mutation. METHODS: A male patient with BPES was identified at the Yale-New Haven Hospital. Following informed consent, clinical data and blood samples from both affected and unaffected family members were obtained. Genomic DNA was extracted from whole blood samples and subjected to exome capture followed by next generation sequencing. Sequence reads were mapped to the human reference genome. Variants with minor allele frequencies in reference databases were selected and annotated for impact on the encoded protein and for conservation of the reference base and amino acid residue among orthologs across phylogeny. Sanger sequencing was employed to verify candidate mutations. In addition, all FOXL2 exons were subjected to Sanger sequencing to verify sequence status. RESULTS: A four-generation BPES pedigree was identified demonstrating autosomal dominant inheritance. In affected individuals, next generation whole exome sequencing identified a common non-sense mutation in ZC3H13 (13q14.13), which was confirmed by Sanger sequencing. A cytosine to thymine (C>T) alteration resulted in the conversion of arginine 1513 to a premature stop codon (R1513X). The variant 13:46538114 C / T was not found in dbSNP with an ExAC allele frequency of 1.651e-05. The amino acid residue arginine 1513 is evolutionarily conserved from Neurospora crassa (red bread mold) to Homo sapiens. All FOXL2 exons lacked disease-causing alterations. Conclusions: ZC3H13 is a putative tumor suppressor gene encoding a zinc finger CCCH-type containing protein. It localizes to nuclear speckles and is predicted to play a role in mRNA splicing and cell cycle progression. Our data suggest that ZC3H13 mutations represent an additional dominant subtype of BPES and point to a novel role for ZC3H13 in craniofacial development and disease pathogenesis. D.M. Balkin: None. C. Nelson-Williams: None. B.J. Sumpio: None. D.A. Scott: None. P. Le Pabic: None. T.F. Schilling: None. R.P. Lifton: None. D. Narayan: None.