Early-Onset Inflammatory Bowel Disease Caused by Mutations in the X-Linked Gene IL2RG

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Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant congenital anomaly syndrome characterized by hairy elbows, dysmorphic facial appearances (hypertelorism, thick eyebrows, downslanted and vertically narrow palpebral fissures), pre- and post-natal growth deficiency, and psychomotor delay. WSS is caused by heterozygous mutations in KMT2A (also known as MLL), a gene encoding a histone methyltransferase. Here, we identify six novel KMT2A mutations in six WSS patients, with four mutations occurring de novo. Interestingly, some of the patients were initially diagnosed with atypical Kabuki syndrome, which is caused by mutations in KMT2D or KDM6A, genes also involved in histone methylation. KMT2A mutations and clinical features are summarized in our six patients together with eight previously reported patients. Furthermore, clinical comparison of the two syndromes is discussed in detail.

A novel de novo point mutation of the OCT-binding site in the IGF2/H19-imprinting control region in a Beckwith-Wiedemann syndrome patient.

The IGF2/H19-imprinting control region (ICR1) functions as an insulator to methylation-sensitive binding of CTCF protein, and regulates imprinted expression of IGF2 and H19 in a parental origin-specific manner. ICR1 methylation defects cause abnormal expression of imprinted genes, leading to Beckwith-Wiedemann syndrome (BWS) or Silver-Russell syndrome (SRS). Not only ICR1 microdeletions involving the CTCF-binding site, but also point mutations and a small deletion of the OCT-binding site have been shown to trigger methylation defects in BWS. Here, mutational analysis of ICR1 in 11 BWS and 12 SRS patients with ICR1 methylation defects revealed a novel de novo point mutation of the OCT-binding site on the maternal allele in one BWS patient. In BWS, all reported mutations and the small deletion of the OCT-binding site, including our case, have occurred within repeat A2. These findings indicate that the OCT-binding site is important for maintaining an unmethylated status of maternal ICR1 in early embryogenesis.

Exome sequencing in a family with an X-linked lethal malformation syndrome: clinical consequences of hemizygous truncating OFD1 mutations in male patients.

Oral-facial-digital syndrome type 1 (OFD1; OMIM #311200) is an X-linked dominant disorder, caused by heterozygous mutations in the OFD1 gene and characterized by facial anomalies, abnormalities in oral tissues, digits, brain, and kidney; and male lethality in the first or second trimester pregnancy. We encountered a family with three affected male neonates having an 'unclassified' X-linked lethal congenital malformation syndrome. Exome sequencing of entire transcripts of the whole X chromosome has identified a novel splicing mutation (c.2388+1G > C) in intron 17 of OFD1, resulting in a premature stop codon at amino acid position 796. The affected males manifested severe multisystem complications in addition to the cardinal features of OFD1 and the carrier female showed only subtle features of OFD1. The present patients and the previously reported male patients from four families (clinical OFD1; Simpson-Golabi-Behmel syndrome, type 2 with an OFD1 mutation; Joubert syndrome-10 with OFD1 mutations) would belong to a single syndrome spectrum caused by truncating OFD1 mutations, presenting with craniofacial features (macrocephaly, depressed or broad nasal bridge, and lip abnormalities), postaxial polydactyly, respiratory insufficiency with recurrent respiratory tract infections in survivors, severe mental or developmental retardation, and brain malformations (hypoplasia or agenesis of corpus callosum and/or cerebellar vermis and posterior fossa abnormalities).

Clinical and genetic features of 20 Japanese patients with vascular-type Ehlers-Danlos syndrome.

BACKGROUND: Vascular-type Ehlers-Danlos syndrome (vEDS) is a severe autosomal dominant inherited disorder resulting from mutations within the α1 type III collagen gene (COL3A1). The majority of published mutations are base changes leading to the substitution of single glycine residues within the triple-helical domain of type III collagen. Although clinical characteristics and mutations in the COL3A1 gene have been analysed for some patients from Europe and America, similar analyses have not yet been performed for Japanese patients with vEDS. OBJECTIVES: To analyse the genetic and phenotypic findings in Japanese patients with vEDS. METHODS: We analysed the clinical features of 20 unrelated individuals with vEDS. To quantify type III collagen production, the fibroblasts were cultured with (3) H-proline, and the radiolabelled collagenous proteins were analysed using sodium dodecyl sulphate-polyacrylamide gel electrophoresis and fluorography. Mutations in COL3A1 were detected by sequence analysis of cDNA from patients' fibroblasts and subsequently by a genomic DNA sequence analysis. RESULTS: Thin and translucent skin with extensive bruising and hypermobility of the small joints were observed in about 90% of the patients, whereas the prevalence of serious clinical findings such as rupture/dissection/aneurysm of the arteries (30%) or rupture of the gastrointestinal tract (25%) was relatively low. Sequence analyses of the COL3A1 gene demonstrated heterozygous point mutations leading to glycine substitution in only nine patients (45%), while heterozygous splice-site mutations at the junction of the triple-helical exons were observed in the remaining 11 patients (55%). The average type III collagen production level in the cultured dermal fibroblasts was 14·6% of the normal value. The types of complication were not associated with specific mutations in COL3A1. CONCLUSION: The analysis in the present series revealed a low frequency of patients presenting with serious clinical findings such as arterial rupture/arterial dissection/aneurysm and perforation or rupture of the gastrointestinal tract, and revealed a higher prevalence of splice-site mutations at the junction of the triple-helical exons than of glycine substitution mutations in COL3A1.

"Ring syndrome" involving chromosome 2 confirmed by FISH analysis using chromosome-specific subtelomeric probes.

"Ring syndrome" is described as those cases with complete ring chromosomes showing, independently of the chromosome involved, severe growth failure, minor dysmorphic features, and mild-to-moderate mental retardation, without major malformations. We present a girl with ring 2 chromosome, exhibiting severe growth failure, minor dysmorphic features, spontaneously closed ventricular septum defect, and normal development. G-banding chromosome analysis and fluorescence in situ hybridization (FISH) analysis using chromosome-specific subtelomeric probes (2ptel, 2qtel) demonstrated the major karyotype as 46,XX,r(2)(p25.3q37.3).ish r(2)(2ptel+,2qtel+). We review the cases with "ring syndrome" confirmed by FISH using chromosome-specific subtelomeric probes, suggesting that this method might be useful to predict developmental prognosis in a case with an apparently complete ring chromosome.