Assessment of gene-disease associations and recommendations for genetic testing for somatic variants in vascular anomalies by VASCERN-VASCA.

Background: Vascular anomalies caused by somatic (postzygotic) variants are clinically and genetically heterogeneous diseases with overlapping or distinct entities. The genetic knowledge in this field is rapidly growing, and genetic testing is now part of the diagnostic workup alongside the clinical, radiological and histopathological data. Nonetheless, access to genetic testing is still limited, and there is significant heterogeneity across the approaches used by the diagnostic laboratories, with direct consequences on test sensitivity and accuracy.

Hereditary palmoplantar keratoderma - phenotypes and mutations in 64 patients.

Background: Hereditary palmoplantar keratodermas (PPK) represent a heterogeneous group of rare skin disorders with epidermal hyperkeratosis of the palms and soles, with occasional additional manifestations in other tissues. Mutations in at least 69 genes have been implicated in PPK, but further novel candidate genes and mutations are still to be found.

Objectives: To identify mutations underlying PPK in a cohort of 64 patients.

Recessive MYH3 variants cause "Contractures, pterygia, and variable skeletal fusions syndrome 1B" mimicking Escobar variant multiple pterygium syndrome.

The multiple pterygium syndromes (MPS) are rare disorders with disease severity ranging from lethal to milder forms. The nonlethal Escobar variant MPS (EVMPS) is characterized by multiple pterygia and arthrogryposis, as well as various additional features including congenital anomalies. The genetic etiology of EVMPS is heterogeneous and the diagnosis has been based either on the detection of pathogenic CHRNG variants (~23% of patients), or suggestive clinical features.

Novel TMEM173 Mutation and the Role of Disease Modifying Alleles.

Upon binding to pathogen or self-derived cytosolic nucleic acids cyclic GMP-AMP synthase (cGAS) triggers the production of cGAMP that further activates transmembrane protein STING. Upon activation STING translocates from ER via Golgi to vesicles. Monogenic STING gain-of-function mutations cause early-onset type I interferonopathy, with disease presentation ranging from fatal vasculopathy to mild chilblain lupus.

Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis.

Familial growth hormone deficiency provides an opportunity to identify new genetic causes of short stature. Here we combine linkage analysis with whole-genome resequencing in patients with growth hormone deficiency and maternally inherited gingival fibromatosis. We report that patients from three unrelated families harbor either of two missense mutations, c.

The Value of FLG Null Mutations in Predicting Treatment Response in Atopic Dermatitis: An Observational Study in Finnish Patients.

The contribution of filaggrin null mutations to predicting atopic dermatitis (AD) treatment response is not clear, nor have such mutations been studied in the Finnish population. This study tested the association of the 4 most prevalent European FLG null mutations, the 2 Finnish enriched FLG null mutations, the FLG 12-repeat allele, and 50 additional epidermal barrier gene variants, with risk of AD, disease severity, clinical features, risk of other atopic diseases, age of onset, and treatment response in 501 patients with AD and 1,710 controls. AD, early-onset AD, palmar hyperlinearity, and asthma showed significant associations with the combined FLG null genotype.

Intrafamily and Interfamilial Phenotype Variation and Immature Immunity in Patients With Netherton Syndrome and Finnish SPINK5 Founder Mutation.

Importance: Netherton syndrome (NS) is a rare and severe genodermatosis caused by SPINK5 mutations leading to the loss of lymphoepithelial Kazal-type-related inhibitor (LEKTI). Netherton syndrome is characterized by neonatal scaling erythroderma, a bamboolike hair defect, a substantial skin barrier defect, and a profound atopic diathesis. Netherton syndrome has been proposed to be a primary immunodeficiency syndrome because of the high frequency of infections.

Identification of SPRED1 deletions using RT-PCR, multiplex ligation-dependent probe amplification and quantitative PCR.

Legius syndrome, is a recently identified autosomal dominant disorder caused by loss of function mutations in the SPRED1 gene, with individuals mainly presenting with multiple café-au-lait macules (CALM), freckling and macrocephaly. So far, only SPRED1 point mutations have been identified as the cause of this syndrome. To determine if copy number changes (CNCs) are a cause of Legius syndrome, we have used a Multiplex Ligation-dependent Probe Amplification (MLPA) assay covering all SPRED1 exons in a cohort of 510 NF1-negative patients presenting with multiple CALMs with or without freckling, but no other NF1 diagnostic signs.

DLX3 homeodomain mutations cause tricho-dento-osseous syndrome with novel phenotypes.

Tricho-dento-osseous syndrome (TDO) is a rare type of dominantly inherited ectodermal dysplasia so far described only in a few families and associated with 3 known mutations in the DLX3 homeobox gene. Here, we describe two families of Finnish origin that segregate features of TDO in several generations. The affected family members have sparse or curly/kinky hair at birth, markedly delayed or advanced dental maturity, defective tooth enamel and dentin, taurodontic molars, multiple dental abscesses and filling of tooth pulps with amorphous denticle-like material as well as an increased density and/or thickness of craniofacial bones.

Epidermolysis Bullosa Simplex with mottled pigmentation: mutation analysis in the first reported Hispanic pedigree with the largest single generation of affected individuals to date.

Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP), characterized by trauma-induced blisters, distinct pigmentary changes of the trunk and extremities, and acral hyperkeratotic papules, is almost exclusively caused by a common KRT5 missense mutation affecting the V1 region of keratin 5. We studied the first Hispanic family, the largest single generation of affected family members in which 5 out of 10 siblings inherited EBS-MP from their affected father, as well a second large pedigree, the first reported of Finnish ancestry. In both families, the heterozygous transition mutation 74C-->T of the keratin 5 gene, which results in amino acid substitution P25L, completely co-segregated with the EBS-MP phenotype.

Rapp-Hodgkin syndrome and the tail of p63.

We report the clinical and molecular abnormalities in a 19-year-old woman with Rapp-Hodgkin ectodermal dysplasia syndrome. The physical features include mid-facial hypoplasia, uncombable hair, cleft palate and bifid uvula, lacrimal duct obstruction and dry skin. Sequencing of the p63 gene reveals a new heterozygous frameshift mutation, 1787delG, in exon 14.

A syndrome with multiple malformations, mental retardation, and ACTH deficiency.

We report on a patient with severe pre- and post-natal growth retardation, moderate mental retardation, microcephaly, unusual face with marked micrognathia and cleft palate, minor skeletal abnormalities, atrioseptal defect, hypospadias, hearing loss, and secondary adrenal insufficiency due to isolated ACTH deficiency diagnosed at 7 years of age. Family history was negative. Adrenal insufficiency is an uncommon feature in multiple malformation syndromes and may thus serve as a diagnostic handle for recognizing other possible patients with a similar syndrome.

Valproate embryopathy in three sets of siblings: further proof of hereditary susceptibility.

The fetal valproate syndrome (FVS) is characterized by distinctive facial appearance, major and minor malformations, and developmental delay. Generally, only a small proportion of prenatally exposed children are affected. The authors describe three families in whom the occurrence of FVS in all the siblings strongly suggests hereditary susceptibility to valproic acid-induced adverse outcome.

Prenatally detected trisomy 7 mosaicism in a dysmorphic child.

Trisomy 7 mosaicism was detected prenatally in cultured amniocytes but not in fetal lymphocytes. The child that was born had pigmentary changes of the skin and facial asymmetry suggestive of a chromosomal mosaicism. Skin fibroblasts were studied and trisomy 7 mosaicism was confirmed.

Splicing mutations in the COL3 domain of collagen IX cause multiple epiphyseal dysplasia.

We report on a three-generation family with multiple epiphyseal dysplasia (MED). The propositus had typical MED findings of knees, ankles, elbows, and hands in childhood. The 2 other affected relatives were adults.

Cytokine modulation of type XV collagen gene expression in human dermal fibroblast cultures.

The expression of type XV collagen was studied in cultured human dermal fibroblasts exposed to transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta (IL-1beta), cytokines which have been shown previously to alter the expression of several extracellular matrix genes. TGF-beta enhanced the expression of the type XV collagen gene (COL15A1) in a time-dependent manner, up to 4.3-fold after 24 h of incubation, whereas TNF-alpha and IL-1beta reduced the mRNA steady-state levels by 32 and 80%, respectively.

Complete exon-intron organization of the human gene for the alpha1 chain of type XV collagen (COL15A1) and comparison with the homologous COL18A1 gene.

The human gene for the alpha1 chain of type XV collagen (COL15A1) is about 145 kilobases in size and contains 42 exons. The promoter is characterized by the lack of a TATAA motif and the presence of several Sp1 binding sites, some of which appeared to be functional in transfected HeLa cells. Comparison with Col18a1, which encodes the alpha1(XVIII) collagen chain homologous with alpha1(XV), indicates marked structural homology spread throughout the two genes.