ABSTRACT
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. The clinical utility of genetic testing is expected to increase progressively with improved theragnostics, which will be based on information about the efficacy and safety of the emerging drugs and future molecules. The aim of this study was to make recommendations for optimising and guiding the diagnostic genetic testing for somatic variants in patients with vascular malformations. RESULTS: Physicians and lab specialists from 11 multidisciplinary European centres for vascular anomalies reviewed the genes identified to date as being involved in non-hereditary vascular malformations, evaluated gene-disease associations, and made recommendations about the technical aspects for identification of low-level mosaicism and variant interpretation. A core list of 24 genes were selected based on the current practices in the participating laboratories, the ISSVA classification and the literature. In total 45 gene-phenotype associations were evaluated: 16 were considered definitive, 16 strong, 3 moderate, 7 limited and 3 with no evidence. CONCLUSIONS: This work provides a detailed evidence-based view of the gene-disease associations in the field of vascular malformations caused by somatic variants. Knowing both the gene-phenotype relationships and the strength of the associations greatly help laboratories in data interpretation and eventually in the clinical diagnosis. This study reflects the state of knowledge as of mid-2023 and will be regularly updated on the VASCERN-VASCA website (VASCERN-VASCA, https://vascern.eu/groupe/vascular-anomalies/ ).
Subject(s)
Genetic Testing , Vascular Malformations , Humans , Genetic Testing/methods , Vascular Malformations/genetics , Vascular Malformations/diagnosis , Vascular Malformations/pathology , Genetic Association StudiesABSTRACT
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. We describe four patients with a clinical suspicion of EVMPS who manifested with multiple pterygia, mild flexion contractures of several joints, and vertebral anomalies. We revealed recessively inherited MYH3 variants as the underlying cause in all patients: two novel variants, c.1053C>G, p.(Tyr351Ter) and c.3102+5G>C, as compound heterozygous with the hypomorphic MYH3 variant c.-9+1G>A. Recessive MYH3 variants have been previously associated with spondylocarpotarsal synostosis syndrome. Our findings now highlight multiple pterygia as an important feature in patients with recessive MYH3 variants. Based on all patients with recessive MYH3 variants reported up to date, we consider that this disease entity should be designated as "Contractures, pterygia, and variable skeletal fusions syndrome 1B," as recently suggested by OMIM. Our findings underline the importance of analyzing MYH3 in the differential diagnosis of EVMPS, particularly as the hypomorphic MYH3 variant might remain undetected by routine exome sequencing.
Subject(s)
Abnormalities, Multiple/genetics , Cytoskeletal Proteins/genetics , Genes, Recessive , Genetic Variation , Malignant Hyperthermia/genetics , Skin Abnormalities/genetics , Child , Child, Preschool , Contracture/genetics , Female , Gene Deletion , Heterozygote , Humans , Lordosis/genetics , Male , Mutation , Pedigree , Phenotype , Scoliosis/genetics , Sequence Analysis, DNA , Siblings , Exome SequencingSubject(s)
Founder Effect , Keratoderma, Palmoplantar/genetics , Serpins/genetics , Adolescent , Adult , Age of Onset , Aged , Child , DNA Mutational Analysis , Female , Finland , Heterozygote , Homozygote , Humans , Keratoderma, Palmoplantar/diagnosis , Keratoderma, Palmoplantar/pathology , Male , Middle Aged , Mutation , Skin/pathology , Exome Sequencing , Young AdultABSTRACT
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. Molecular mechanisms underlying the variable phenotype-genotype correlation are presently unclear. Here, we report a novel gain-of-function G207E STING mutation causing a distinct phenotype with alopecia, photosensitivity, thyroid dysfunction, and features of STING-associated vasculopathy with onset in infancy (SAVI), such as livedo reticularis, skin vasculitis, nasal septum perforation, facial erythema, and bacterial infections. Polymorphism in TMEM173 and IFIH1 showed variable penetrance in the affected family, implying contribution to varying phenotype spectrum. The G207E mutation constitutively activates inflammation-related pathways in vitro, and causes aberrant interferon signature and inflammasome activation in patient PBMCs. Treatment with Janus kinase 1 and 2 (JAK1/2) inhibitor baricitinib was beneficiary for a vasculitic ulcer, induced hair regrowth and improved overall well-being in one patient. Protein-protein interactions propose impaired cellular trafficking of G207E mutant. These findings reveal the molecular landscape of STING and propose common polymorphisms in TMEM173 and IFIH1 as likely modifiers of the phenotype.
Subject(s)
Alleles , Genetic Association Studies , Genetic Predisposition to Disease , Interferon-Induced Helicase, IFIH1/genetics , Membrane Proteins/genetics , Mutation , Case-Control Studies , Consanguinity , Female , Gene Expression Profiling , Genetic Linkage , Humans , Male , Pedigree , Transcriptome , Whole Genome SequencingABSTRACT
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.347G>T p.(Arg116Leu) or c.1106C>T p.(Pro369Leu), in KCNQ1, a gene previously implicated in the long QT interval syndrome. Kcnq1 is expressed in hypothalamic GHRH neurons and pituitary somatotropes. Co-expressing KCNQ1 with the KCNE2 ß-subunit shows that both KCNQ1 mutants increase current levels in patch clamp analyses and are associated with reduced pituitary hormone secretion from AtT-20 cells. In conclusion, our results reveal a role for the KCNQ1 potassium channel in the regulation of human growth, and show that growth hormone deficiency associated with maternally inherited gingival fibromatosis is an allelic disorder with cardiac arrhythmia syndromes caused by KCNQ1 mutations.
Subject(s)
Fibromatosis, Gingival/genetics , Human Growth Hormone/deficiency , KCNQ1 Potassium Channel/genetics , Mutation, Missense , Adolescent , Adrenocorticotropic Hormone/metabolism , Adult , Alleles , Amino Acid Substitution , Animals , Arrhythmias, Cardiac/genetics , Child , Child, Preschool , Female , Fibromatosis, Gingival/metabolism , Humans , KCNQ1 Potassium Channel/chemistry , KCNQ1 Potassium Channel/metabolism , Male , Maternal Inheritance/genetics , Mice , Middle Aged , Models, Molecular , Pedigree , Protein Interaction Maps , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Young AdultABSTRACT
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. Disease severity and treatment response were independent of patient FLG status. Carrier frequencies of R501X, 2282del4, and S3247X were notably lower in Finns compared with reported frequencies in other populations. This data confirms FLG mutations as risk factors for AD in Finns, but also questions their feasibility as biomarkers in predicting treatment response.
Subject(s)
Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/genetics , Immunosuppressive Agents/therapeutic use , Intermediate Filament Proteins/genetics , Mutation , Pharmacogenomic Variants , Adolescent , Adult , Case-Control Studies , Dermatitis, Atopic/diagnosis , Female , Filaggrin Proteins , Finland , Gene Frequency , Genetic Predisposition to Disease , Heterozygote , Homozygote , Humans , Male , Middle Aged , Pharmacogenetics , Phenotype , Prospective Studies , Severity of Illness Index , Treatment Outcome , Young AdultABSTRACT
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. The precise mechanisms underlying the disease are not fully understood. OBJECTIVE: To study the association of the SPINK5 mutation with the NS phenotype and the extent of immunologic deficiencies in NS. DESIGN, SETTING, AND PARTICIPANTS: Relevant tissue samples and follow-up data from 11 patients with NS from 7 families, including 3 multiplex families, were collected, constituting all known patients with NS in Finland. Another patient with NS from a neighboring country was included. Data were collected from August 10, 2011, to February 20, 2015. SPINK5 mutations were sequenced, and thorough clinical evaluation and histopathologic and immunohistochemical evaluations of skin samples were performed. The function of natural killer cells, lymphocyte phenotype, and serum immunoglobulin subclass levels were evaluated. Data analysis was conducted from October 19, 2011, to February 20, 2015. MAIN OUTCOMES AND MEASURES: The nature of SPINK5 mutations and their correlation with phenotypes in Finnish patients with NS, intrafamilial phenotype variations, and the type of immunologic defects in NS were evaluated. RESULTS: Among the 11 Finnish patients with NS (8 male [73%]; 3 female [27%]; mean [SD] age, 30.1 [9.1] years), a Finnish founder mutation c.652C>T (p.Arg218*) in SPINK5 was identified in 10 patients from 6 families who all originated from the same region. Eight patients were homozygotes for this mutation and 2 siblings were compound heterozygotes with a splice site mutation c.1220 + 1G>C (IVS13 + 1 G>C). Phenotypes were comparable, but some intrafamilial and interfamilial variations were noted. Compound heterozygous patients had a milder phenotype and showed residual LEKTI expression. A previously unreported c.1772delT (p.Leu591Glnfs124*) mutation was found in 1 patient with a phenotype similar to the patients homozygous for the founder mutation. The patient from the neighboring country had a distinct phenotype and different mutations. Immunologically, natural killer cells had an immature phenotype and impaired cytotoxicity and degranulation, levels of memory B cells were reduced, and serum IgG4 levels were elevated. Intravenous immunoglobulin treatment has been beneficial in 1 patient with NS. CONCLUSIONS AND RELEVANCE: This report discloses a prevalent SPINK5 founder mutation in Finland and illustrates NS phenotype variability. Our results also point to a possible role of immature immunity in the frequent infections seen in NS.
Subject(s)
B-Lymphocytes/immunology , Family Health , Killer Cells, Natural/immunology , Proteinase Inhibitory Proteins, Secretory/genetics , Child , Child, Preschool , Female , Finland , Follow-Up Studies , Humans , Immunoglobulin G/blood , Infant , Male , Mutation , Netherton Syndrome/genetics , Netherton Syndrome/immunology , Netherton Syndrome/physiopathology , Phenotype , Serine Peptidase Inhibitor Kazal-Type 5Subject(s)
Allergens/immunology , Dermatitis, Atopic/diagnosis , Epidermis/metabolism , Immunoglobulin E/immunology , Netherton Syndrome/diagnosis , Proteinase Inhibitory Proteins, Secretory/metabolism , Adolescent , Child , Child, Preschool , Dermatitis, Atopic/genetics , Dermatitis, Atopic/immunology , Epidermis/pathology , Female , Finland , Food/adverse effects , Humans , Immunoglobulin E/blood , Male , Microarray Analysis , Middle Aged , Mutation/genetics , Netherton Syndrome/genetics , Netherton Syndrome/immunology , Profilins/adverse effects , Profilins/analysis , Profilins/immunology , Proteinase Inhibitory Proteins, Secretory/genetics , Serine Peptidase Inhibitor Kazal-Type 5ABSTRACT
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. Four different deletions were identified by MLPA and confirmed by quantitative PCR, reverse transcriptase PCR and/or array CGH: a deletion of exon 1 and the SPRED1 promoter region in a proband and two first-degree relatives; a deletion of the entire SPRED1 gene in a sporadic patient; a deletion of exon 2-6 in a proband and her father; and an â¼6.6 Mb deletion on chromosome 15 that spans SPRED1 in a sporadic patient. Deletions account for â¼10% of the 40 detected SPRED1 mutations in this cohort of 510 individuals. These results indicate the need for dosage analysis to complement sequencing-based SPRED1 mutation analyses.
Subject(s)
Cafe-au-Lait Spots/genetics , Gene Dosage/genetics , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Sequence Deletion/genetics , Adaptor Proteins, Signal Transducing , Comparative Genomic Hybridization , DNA Primers/genetics , Humans , Nucleic Acid Amplification Techniques/methods , Polymerase Chain Reaction/methods , Reverse Transcriptase Polymerase Chain ReactionSubject(s)
Cell Cycle Proteins/genetics , Hodgkin Disease/genetics , Adolescent , Adult , Aged , Female , Genetic Predisposition to Disease , Humans , Immunophenotyping , Male , Middle Aged , Pedigree , Polymorphism, Single Nucleotide , Young AdultABSTRACT
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. The disease is especially accentuated in one of the families in which the patients develop only lanugo-type hair and the dental abnormalities are severe. After mutational analysis of DLX3, we identified 2 missense mutations affecting the conserved homeodomain. We suggest that TDO is essentially caused by loss of function and haploinsufficiency of DLX3.
Subject(s)
Dental Enamel Hypoplasia/genetics , Hair Diseases/genetics , Homeodomain Proteins/genetics , Mutation , Phenotype , Transcription Factors/genetics , Amino Acid Sequence , Base Sequence , Craniofacial Abnormalities , DNA Mutational Analysis , Family , Finland , Genes, Homeobox , Haploinsufficiency , Humans , Molecular Sequence DataABSTRACT
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.
Subject(s)
Epidermolysis Bullosa Simplex/complications , Epidermolysis Bullosa Simplex/genetics , Hispanic or Latino , Pigmentation Disorders/complications , Pigmentation Disorders/genetics , Adolescent , Adult , Child , Child, Preschool , DNA Mutational Analysis , Female , Humans , Male , Middle Aged , PedigreeABSTRACT
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.
Subject(s)
Abnormalities, Multiple/genetics , Adrenocorticotropic Hormone/deficiency , Intellectual Disability/genetics , Adrenal Gland Diseases/genetics , Adult , Child , Developmental Disabilities , Face/abnormalities , Female , Humans , Male , Microcephaly/genetics , SyndromeABSTRACT
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. At 3 years of age the boy had developed mentally within normal limits. However, dysmorphic findings include sparse hair, short left palpebral fissure, ptosis of the left eyelid, strabismus, enamel dysplasia, low-set and posteriorly rotated ears and undescended testes. These findings share some common features with previously reported cases of trisomy 7 mosaicism.