A novel small deletion in the NHS gene associated with Nance-Horan syndrome.

Nance-Horan syndrome is a rare X-linked recessive inherited disease with clinical features including severe bilateral congenital cataracts, characteristic facial and dental abnormalities. Data from Chinese Nance-Horan syndrome patients are limited. We assessed the clinical manifestations of a Chinese Nance-Horan syndrome pedigree and identified the genetic defect. Genetic analysis showed that 3 affected males carried a novel small deletion in NHS gene, c.263_266delCGTC (p.Ala89TrpfsTer106), and 2 female carriers were heterozygous for the same variant. All 3 affected males presented with typical Nance-Horan syndrome features. One female carrier displayed lens opacities centered on the posterior Y-suture in both eyes, as well as mild dental abnormalities. We recorded the clinical features of a Chinese Nance-Horan syndrome family and broadened the spectrum of mutations in the NHS gene.

X-linked Sideroblastic Anemia in a Malay Boy With ALAS2 S568G Mutation.

Dimorphism in peripheral blood film was noted in a 16 year old Malay boy with anemia who was eventually diagnosed with X-linked sideroblastic anemia. A mutation in ALAS2 S568G was identified which has not been described previously in a Malay ethnic group.

NHS Gene Mutations in Ashkenazi Jewish Families with Nance-Horan Syndrome.

PURPOSE: To describe ocular and extraocular abnormalities in two Ashkenazi Jewish families with infantile cataract and X-linked inheritance, and to identify their underlying mutations. METHODS: Seven affected members were recruited. Medical history, clinical findings, and biometric measurements were recorded. Mutation analysis of the Nance-Horan syndrome (NHS) gene was performed by direct sequencing of polymerase chain reaction-amplified exons. RESULTS: An unusual anterior Y-sutural cataract was documented in the affected male proband. Other clinical features among examined patients included microcorneas, long and narrow faces, and current or previous dental anomalies. A nonsense mutation was identified in each family, including a previously described 742 C>T, p.(Arg248*) mutation in Family A, and a novel mutation 2915 C>A, p.(Ser972*) in Family B. CONCLUSIONS: Our study expands the repertoire of NHS mutations and the related phenotype, including newly described anterior Y-sutural cataract and dental findings.

Dysgammaglobulinemia Associated With Glu349del, a Hypomorphic XIAP Mutation.

BACKGROUND: X-linked lymphoproliferative syndrome type 2 is a rare hereditary immunodeficiency caused by mutations in the XIAP gene. This immunodeficiency frequently results in hemophagocytic lymphohistiocytosis, although hypogammaglobulinemia and dysgammaglobulinemia are also common. OBJECTIVE: We identified 17 patients from 12 Japanese families with mutations in XIAP. The Glu349del mutation was observed in 3 patients, each from a different family. Interestingly, these patients exhibited dysgammaglobulinemia but not hemophagocytic lymphohistiocytosis. We conducted an immunological study of patients carrying Glu349del and other mutations to elucidate the pathogenic mechanisms of dysgammaglobulinemia in patients with mutations in the XIAP gene. PATIENTS AND METHODS: We performed an immunological study of 2 patients carrying the Glu349del mutation and 8 patients with other mutations. RESULTS: Flow cytometry showed that the percentage of memory B cells in patients with a mutation in XIAP was lower than that observed in the healthy controls. The patients with the Glu349del mutation had a lower percentage of memory B cells than those with other mutations. Ig production was reduced in patients with the Glu349del mutation. Increased susceptibility to apoptosis was observed in the patients with other mutations. Susceptibility to apoptosis was normal in patients with Glu349del. Microarray analysis indicated that expression of Ig-related genes was reduced in patients with the Glu349del mutation and that the pattern was different from that observed in the healthy controls or patients with other mutations in XIAP. CONCLUSIONS: Patients carrying the Glu349del mutation in the XIAP gene may have a clinically and immunologically distinct phenotype from patients with other XIAP mutations. The Glu349del mutation may be associated with dysgammaglobulinemia.

A novel splicing mutation in the SEDL gene causes spondyloepiphyseal dysplasia tarda in a large Chinese pedigree.

The X-linked form of spondyloepiphyseal dysplasia tarda (SEDT, OMIM# 313400) is a rare osteochondrodysplasia caused by mutations in the SEDL (TRAPPC2, OMIM# 300202) gene. It is clinically characterized by disproportionate short stature, barrel-shaped chests and early development of degenerative joint disease. We report here a novel mutation in the intron 3 splice-donor site (c. 93+5G>C) segregated in an X-link pattern in a large Chinese family with SEDT. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that the mutation causes an aberrant splicing of exon 3, resulting in the elimination of 31 codons in the exon and a considerable loss function of the SEDL protein. This mutation was not detected in the 100 healthy controls. This novel mutation adds to the spectrum of previously-identified disease-causing mutations. Pre-symptomatic molecular diagnosis and prenatal diagnosis of the pregnant carriers could be helpful to families with SEDT.

Co-morbidity of Emery-Dreifuss muscular dystrophy and a congenital myasthenic syndrome possibly affecting the phenotype in a large Bedouin kindred.

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked humero-peroneal muscular dystrophy associated with contractures and cardiomyopathy. In a 90 member family, we found 11 affected male individuals, three of whom displayed areflexia and neurogenic electromyographic changes. Muscle biopsy performed in one case demonstrated type grouping suggestive of a neurogenic disorder. These three individuals and another family member, who suffers from mild, static limb weakness but is clinically and genetically unaffected by EDMD showed an abnormal incremental response of over 100% to tetanic stimulation. In contrast, one affected family member showed myopathic features on needle electromyography and no definite pathology in repetitive stimulation studies. The diagnosis of EDMD was established by demonstrating a 1712_1713insTGGGC mutation in the emerin gene. This family apparently expresses co-morbidity of EDMD with an exceptionally mild form of pre-synaptic congenital myasthenic syndrome resembling the Lambert-Eaton myasthenic syndrome (LEMS). The superimposed pre-synaptic disorder may have contributed to the development of the neurogenic features demonstrated in these patients.