Identification of two novel ATP6V0A2 mutations in an infant with cutis laxa by exome sequencing

Cutis laxa (CL) refers to a group of rare connective tissue disorders challenging to diagnose because of their different inheritance pattern, extensive phenotypic variability, and genetic heterogeneity. In this study, we performed whole exome sequencing of an Italian seven-month-old infant with generalized, sagging, redundant skin cutis laxa type, delayed fontanelle closure, borderline microcephaly, dysmorphisms, and without current neurological involvement. Bioinformatics filtering of the variants in known CL genes allowed the identification of two novel loss-of-function mutations in the ATP6V0A2 gene, leading to the diagnosis of autosomal recessive CL type 2A (ARCL2A). Segregation analysis by Sanger sequencing revealed that the c.534delC and c.1002delT small deletions were inherited from the unaffected father and mother, respectively. Our molecular findings, obtained through the powerful exome sequencing approach, expand the knowledge of the clinical phenotype and the allelic repertoire of ARCL2A

Compound heterozygosity of the novel 186C>T mutation in the COL7A1 promoter and the recurrent c.497insA mutation leads to generalized dystrophic epidermolysis bullosa

Dystrophic epidermolysis bullosa (DEB) is a rare genodermatosis characterised by trauma-induced blister formation beneath the lamina densa in the papillary dermis. Other clinical findings include atrophic scarring, milia formation, fusion of digits, nail dystrophy and contractures. DEB comprises 13 variants with different mucocutaneous involvement. All variants result from either dominant or recessive (RDEB) mutations in the COL7A1 gene, which encodes type VII collagen (COLVII). COLVII is the major component of anchoring fibrils (AFs), which ensure dermal–epidermal adhesion. To date, 636 distinct mutations throughout this gene have been reported, and general genotype–phenotype correlations have been defined. Here, we report an Italian RDEB patient (generalised subtype) with a mild phenotype who is compound heterozygous for a novel -186C>T mutation in the COL7A1 promoter and the recurrent c.497insA mutation. The -186C>T mutation is the second in the COL7A1 promoter reported to date; the first was the -187C>T identified in heterozygosity in a patient with severe generalised RDEB phenotype. Both mutations are in the same consensus sequence for the Sp1 transcription factor, but they have different effects on COL7A1 transcription, therefore producing different clinical phenotypes. This work underlines that COL7A1 promoter mutation are very rare, but this region should be investigated in RDEB patients with only a heterozygous mutation identified

Insights in the etiopathology of galactosyltransferase II (GalT-II) deficiency from transcriptome-wide expression profiling of skin fibroblasts of two sisters with compound heterozygosity for two novel B3GALT6 mutations

Mutations in B3GALT6, encoding the galactosyltransferase II (GalT-II) involved in the synthesis of the glycosaminoglycan (GAG) linkage region of proteoglycans (PGs), have recently been associated with a spectrum of connective tissue disorders, including spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1) and Ehlers–Danlos-like syndrome. Here, we report on two sisters compound heterozygous for two novel B3GALT6 mutations that presented with severe short stature and progressive kyphoscoliosis, joint hypermobility and laxity, hyperextensible skin, platyspondyly, short ilia, and elbow malalignment. Microarray-based transcriptome analysis revealed the differential expression of several genes encoding extracellular matrix (ECM) structural components, including COMP, SPP1, COL5A1, and COL15A1, enzymes involved in GAG synthesis and in ECM remodeling, such as CSGALNACT1, CHPF, LOXL3, and STEAP4, signaling transduction molecules of the TGFβ/BMP pathway, i.e., GDF6, GDF15, and BMPER, and transcription factors of the HOX and LIM families implicated in skeletal and limb development. Immunofluorescence analyses confirmed the down-regulated expression of some of these genes, in particular of the cartilage oligomeric matrix protein and osteopontin, encoded by COMP and SPP1, respectively, and showed the predominant reduction and disassembly of the heparan sulfate specific GAGs, as well as of the PG perlecan and type III and V collagens. The key role of GalT-II in GAG synthesis and the crucial biological functions of PGs are consistent with the perturbation of many physiological functions that are critical for the correct architecture and homeostasis of various connective tissues, including skin, bone, cartilage, tendons, and ligaments, and generates the wide phenotypic spectrum of GalT-II-deficient patients

Arterial Tortuosity Syndrome: Homozygosity for two novel and one recurrent SLC2A10 missense mutations in three families with severe cardiopulmonary complications in infancy and a literature review

BackgroundArterial Tortuosity Syndrome (ATS) is a very rare autosomal recessive connective tissue disorder (CTD) characterized by tortuosity and elongation of the large- and medium-sized arteries and a propensity for aneurysm formation and vascular dissection. During infancy, children frequently present the involvement of the pulmonary arteries (elongation, tortuosity, stenosis) with dyspnea and cyanosis. Other CTD signs of ATS are dysmorphisms, abdominal hernias, joint hypermobility, skeletal abnormalities, and keratoconus. ATS is typically described as a severe disease with high rate of mortality due to major cardiovascular malformations. ATS is caused by mutations in the SLC2A10 gene, which encodes the facilitative glucose transporter 10 (GLUT10). Approximately 100 ATS patients have been described, and 21 causal mutations have been identified in the SLC2A10 gene.Case presentationWe describe the clinical findings and molecular characterization of three new ATS families, which provide insight into the clinical phenotype of the disorder; furthermore, we expand the allelic repertoire of SLC2A10 by identifying two novel mutations. We also review the ATS patients characterized by our group and compare their clinical findings with previous data.ConclusionsOur data confirm that the cardiovascular prognosis in ATS is less severe than previously reported and that the first years of life are the most critical for possible life-threatening events. Molecular diagnosis is mandatory to distinguish ATS from other CTDs and to define targeted clinical follow-up and timely cardiovascular surgical or interventional treatment, when needed