A case of spondyloepiphyseal dysplasia tarda caused by a novel intragenic deletion of TRAPPC2.

Introduction

Spondyloepiphyseal dysplasia tarda (SEDT; MIM # 313400) is a rare X-linked recessive skeletal disease characterized by disproportionate short stature with vertebral malformation and degenerative changes involving the spine and major joints (1). During infancy and early childhood, affected males show normal development and unremarkable findings on radiographs (1). Clinical expression of SEDT begins with a flattening of the growth curve before puberty. At this time, radiographs show characteristic deformities of the vertebrae, including platyspondyly with a posterior hump. Degenerative joint disease is a common problem in male patients making hip joint replacement often necessary in the fourth or fifth decade of life (2).

The causative gene of SEDT is TRAPPC2, which encodes trafficking protein particle complex subunit 2, a 140 amino acid protein, also known as Sedlin. TRAPPC2 may play a role in vesicular transport from the endoplasmic reticulum to the Golgi (3, 4). To date, 50 TRAPPC2 mutations have been reported in families with SEDT of different ethnic origin (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/ac). The underlying mutations are spread over the entire coding region of the TRAPPC2 gene comprising exons 3-6, without clear genotype-phenotype correlation. Here, we report a Japanese SEDT patient with a novel intragenic deletion mutation in TRAPPC2.

Patient Report

The propositus was a 15-yr-old Japanese male, who was born at 39 wk of gestation after an uncomplicated pregnancy and delivery. He was the second child of nonconsanguineous healthy parents (Fig. 1). At birth, his length was 50.0 cm (+ 0.5 SD), and his weight was 3.28 kg (+ 0.7 SD). He was referred to us at 10 yr of age because of short stature. His height was 110.5 cm (–4.5 SD), and his weight was 20.7 kg (–1.7 SD). His trunk was disproportionately short. The longitudinal growth record of the patient is shown in Fig. 1. The patient’s facial features were unremarkable, and his serum concentrations of insulin-like growth factor 1 and thyroid hormone were normal. Radiographs showed platyspondyly with a posterior hump of the vertebral bodies, while the pelvis and tubular bones were normal (Fig. 1). A diagnosis of SEDT was made, based on the late onset of disproportionately short stature with short trunk and radiological findings. At 12 yr of age, his height was 114.8 cm (–4.9 SD), his weight was 22.3 kg (–1.9 SD), and his arm span was 121.5 cm. At his last examination at the age of 14 yr and 8 mo, his height was 122.8 cm (–6.8 SD), his weight was 25.9 kg (–2.9 SD), and his arm span was 128 cm. The father of the patient was 155.0 cm (–2.7 SD) tall, and the mother was 163.0 cm (0.9 SD) tall.

Fig. 1.

Characterization of the patient. (A) Pedigree and longitudinal growth record of the Japanese patient with SEDT. (B) Radiographs of the patient at 14 yr of age. Radiographs of the lateral lumbosacral spine (left) showed platyspondyly (arrows) with a posterior hump of the vertebral bodies (arrowheads). The pelvis (right) was normal.

Mutational Analysis

After obtaining informed consent, and with the approval of the Institutional Review Board of Keio University School of Medicine, genomic DNA was extracted from the patient’s peripheral blood leukocytes. We checked all four coding exons (exons 3-6) and flanking introns of TRAPPC2 by PCR-direct sequencing. We failed to amplify exons 4 and 5 from the patient, whereas exons 3 and 6 from the patient and all 4 exons from the control DNA were successfully amplified. Then, we performed long-range PCR encompassing exons 4-6. Gel electrophoresis of the PCR products showed a smaller fragment than expected in the patient (Fig. 2A). Sequencing of the mutant fragment revealed a 693-bp deletion, which started in exon 4 and ended in intron 5 (c.197_324+121del693bp) (Fig. 2B). No other family member was available for genetic studies.

Fig. 2.

Identification of a 693 bp intragenic deletion in TRAPPC2. (A) To determine the size and possible location of the deletion, primers encompassing exons 4–6 were used. A size difference of 693 bp was apparent. Lanes 1, negative control; lane 2, Control; lane 3, Patient. (B) Schema of the TRAPPC2 genomic organization and partial sequences of PCR products of the patient are shown.

Discussion

We report a case of SEDT with partial deletion in TRAPPC2. The TRAPPC2 deletion that we identified is novel and has not been registered as a frequent nonpathogenic copy number variations in existing databases, including the Database of Genomic Variants, DECIPHER and UCSC. The abnormal transcript from this mutant TRAPPC2 would generate, if translated, a protein lacking one-fifth of TRAPPC2. Although the functional consequence of this deletion has not been determined in vitro, we believe that this deletion is pathological.

Since first described by Gedeon et al. in 1999 (3), 50 mutations of TRAPPC2 have been reported, without clear genotype-phenotype correlation. Our findings provide additional evidence that helps us better understand the pathogenesis of TRAPPC2 in SEDT. Clinical characterization of further mutations including deletion cases is necessary to correlate genotype to phenotype.