Exome capture and massively parallel sequencing identifies a novel HPSE2 mutation in a Saudi Arabian child with Ochoa (urofacial) syndrome

Abstract

We describe a child of Middle Eastern descent by first-cousin coupling with idiopathic neurogenic bladder and high-grade vesicoureteral reflux at 1 year of age, whose characteristic facial grimace led to the diagnosis of Ochoa (urofacial) syndrome at age 5 years. We used homozygosity mapping, exome capture and paired-end sequencing to identify the disease causing mutation in the proband. We reviewed the literature with respect to the urologic manifestations of Ochoa syndrome. A large region of marker homozygosity was observed at 10q24, consistent with known autosomal recessive inheritance, family consanguinity and previous genetic mapping in other families with Ochoa syndrome. A homozygous mutation was identified in the proband in HPSE2: c.1374_1378delTGTGC, a deletion of 5 nucleotides in exon 10 that is predicted to lead to a frameshift followed by replacement of 132 C-terminal amino acids with 153 novel amino acids (p.Ala458Alafsdel132ins153). This mutation is novel relative to very recently published mutations in HPSE2 in other families. Early intervention and recognition of Ochoa syndrome with control of risk factors and close surveillance will decrease complications and renal failure.

Figure 1

Radiographic documentation of vesicoureteral reflux. Voiding cystourethogram showing neurogenic bladder with a trabeculated, thickened bladder wall and increased bladder capacity. During filling a bilateral grade five reflux into the palvicalceal system was evident.

Figure 2

Photograph of proband at 9 years old. Note characteristic facial grimace, which occurs when laughing or smiling.

Figure 3

Paired-end sequencing identifies HPSE2 deletion. Genome Analysis Toolkit screen shot of a portion of HPSE2 exon 10 showing 36 base pair reads with a 5 base pair deletion (gap between the grey bars) encountered in 7/9 reads.

Figure 4

Confirmation of paired-end sequencing result using Sanger sequencing. PCR amplification and sequencing of genomic DNA from the affected proband and her parents revealed that she is homozygous for the 5 base pair deletion and confirms the high-throughput sequencing data. TOP: Sequence confirming homozygous deletion in proband. Dark vertical bar represents position of homozygous deletion of TGTGC. MIDDLE: Sequence of paternal PCR-amplified, cloned deleted allele. BOTTOM: Sequence of paternal PCR-amplified, cloned non-deleted allele; TGTGC is deleted in chromatograms shown in TOP and MIDDLE. Maternal PCR-amplified products revealed both deleted and non-deleted products identical to the paternal products shown. The mutated sequence demonstrating the deletion has been submitted to GenBank, submission number 1402171.