RESUMEN
Hyperferritinemia is a frequent finding in several conditions, both genetic and acquired. We previously studied eleven healthy subjects from eight different families presenting with unexplained hyperferritinemia. Their findings suggested the existence of an autosomal-recessive disorder. We carried out whole-exome sequencing to detect the genetic cause of hyperferritinemia. Immunohistochemistry and flow cytometry assays were performed on liver biopsies and monocyte-macrophages to confirm the pathogenic role of the identified candidate variants. Through a combined approach of whole-exome sequencing and homozygosity mapping, we found bi-allelic STAB1 variants in ten subjects from seven families. STAB1 encodes the multifunctional scavenger receptor stabilin-1. Immunohistochemistry and flow cytometry analyses showed absent or markedly reduced stabilin-1 in liver samples, monocytes, and monocyte-derived macrophages. Our findings show a strong association between otherwise unexplained hyperferritinemia and bi-allelic STAB1 mutations suggesting the existence of another genetic cause of hyperferritinemia without iron overload and an unexpected function of stabilin-1 in ferritin metabolism.
Asunto(s)
Hiperferritinemia , Sobrecarga de Hierro , Humanos , Sobrecarga de Hierro/genética , Sobrecarga de Hierro/diagnóstico , Ferritinas/genética , Macrófagos , AlelosRESUMEN
Deleterious variants in collagen genes are the most common cause of hereditary connective tissue disorders (HCTD). Adaptations of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria are still lacking. A multidisciplinary team was set up for developing specifications of the ACMG/AMP criteria for COL1A1, COL1A2, COL2A1, COL3A1, COL5A1, COL5A2, COL11A1, COL11A2 and COL12A1, associated with various forms of HCTD featuring joint hypermobility, which is becoming one of the most common reasons of referral for molecular testing in this field. Such specifications were validated against 209 variants, and resulted effective for classifying as pathogenic and likely pathogenic null alleles without downgrading of the PVS1 level of strength and recurrent Glycine substitutions. Adaptations of selected criteria reduced uncertainties on private Glycine substitutions, intronic variants predicted to affect the splicing, and null alleles with a downgraded PVS1 level of strength. Segregation and multigene panel sequencing data mitigated uncertainties on non-Glycine substitutions by the attribution of one or more benignity criteria. These specifications may improve the clinical utility of molecular testing in HCTD by reducing the number of variants with neutral/conflicting interpretations. Close interactions between laboratory and clinicians are crucial to estimate the a priori utility of molecular test and to improve medical reports.
Asunto(s)
Variación Genética , Inestabilidad de la Articulación , Humanos , Estados Unidos , Pruebas Genéticas/métodos , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/genética , Análisis de Secuencia de ADN/métodosRESUMEN
PURPOSE: The SF3B splicing complex is composed of SF3B1-6 and PHF5A. We report a developmental disorder caused by de novo variants in PHF5A. METHODS: Clinical, genomic, and functional studies using subject-derived fibroblasts and a heterologous cellular system were performed. RESULTS: We studied 9 subjects with congenital malformations, including preauricular tags and hypospadias, growth abnormalities, and developmental delay who had de novo heterozygous PHF5A variants, including 4 loss-of-function (LOF), 3 missense, 1 splice, and 1 start-loss variant. In subject-derived fibroblasts with PHF5A LOF variants, wild-type and variant PHF5A mRNAs had a 1:1 ratio, and PHF5A mRNA levels were normal. Transcriptome sequencing revealed alternative promoter use and downregulated genes involved in cell-cycle regulation. Subject and control fibroblasts had similar amounts of PHF5A with the predicted wild-type molecular weight and of SF3B1-3 and SF3B6. SF3B complex formation was unaffected in 2 subject cell lines. CONCLUSION: Our data suggest the existence of feedback mechanisms in fibroblasts with PHF5A LOF variants to maintain normal levels of SF3B components. These compensatory mechanisms in subject fibroblasts with PHF5A or SF3B4 LOF variants suggest disturbed autoregulation of mutated splicing factor genes in specific cell types, that is, neural crest cells, during embryonic development rather than haploinsufficiency as pathomechanism.
Asunto(s)
Anomalías Craneofaciales , Hipospadias , Masculino , Humanos , Hipospadias/genética , Factores de Empalme de ARN/genética , Empalme del ARN , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transactivadores/genética , Proteínas de Unión al ARN/genéticaRESUMEN
Two adult siblings born to first-cousin parents presented a clinical phenotype reminiscent of Rothmund-Thomson syndrome (RTS), implying fragile hair, absent eyelashes/eyebrows, bilateral cataracts, mottled pigmentation, dental decay, hypogonadism, and osteoporosis. As the clinical suspicion was not supported by the sequencing of RECQL4, the RTS2-causative gene, whole exome sequencing was applied and disclosed the homozygous variants c.83G>A (p.Gly28Asp) and c.2624A>C (p.Glu875Ala) in the nucleoporin 98 (NUP98) gene. Though both variants affect highly conserved amino acids, the c.83G>A looked more intriguing due to its higher pathogenicity score and location of the replaced amino acid between phenylalanine-glycine (FG) repeats within the first NUP98 intrinsically disordered region. Molecular modeling studies of the mutated NUP98 FG domain evidenced a dispersion of the intramolecular cohesion elements and a more elongated conformational state compared to the wild type. This different dynamic behavior may affect the NUP98 functions as the minor plasticity of the mutated FG domain undermines its role as a multi-docking station for RNA and proteins, and the impaired folding can lead to the weakening or the loss of specific interactions. The clinical overlap of NUP98-mutated and RTS2/RTS1 patients, accounted by converging dysregulated gene networks, supports this first-described constitutional NUP98 disorder, expanding the well-known role of NUP98 in cancer.
Asunto(s)
Mutación de Línea Germinal , Proteínas de Complejo Poro Nuclear , Síndrome Rothmund-Thomson , Humanos , Proteínas de Complejo Poro Nuclear/química , Proteínas de Complejo Poro Nuclear/genética , Síndrome Rothmund-Thomson/genética , Hermanos , Masculino , Femenino , Conformación ProteicaRESUMEN
Biallelic pathogenic variants in POC1A result in SOFT (Short-stature, Onychodysplasia, Facial-dysmorphism, and hypoTrichosis) and variant POC1A-related (vPOC1A) syndromes. The latter, nowadays described in only two unrelated subjects, is associated with a restricted spectrum of variants falling in exon 10, which is naturally skipped in a specific POC1A mRNA. The synthesis of an amount of a POC1A isoform from this transcript in individuals with vPOC1A syndrome has been believed as the likely explanation for such a genotype-phenotype correlation. Here, we illustrate the clinical and molecular findings in a woman who resulted to be compound heterozygous for a recurrent frameshift variant in exon 10 and a novel variant in exon 9 of POC1A. Phenotypic characteristics of this woman included severe hyperinsulinemic dyslipidemia, acanthosis nigricans, moderate growth restriction, and dysmorphisms. These manifestations overlap the clinical features of the two previously published individuals with vPOC1A syndrome. RT-PCR analysis on peripheral blood and subsequent sequencing of the obtained amplicons demonstrated a variety of POC1A alternative transcripts that resulted to be expressed in the proband, in the healthy mother, and in controls. We illustrate the possible consequences of the two POC1A identified variants in an attempt to explain pleiotropy in vPOC1A syndrome.
Asunto(s)
Proteínas de Ciclo Celular/genética , Hiperinsulinismo Congénito/genética , Proteínas del Citoesqueleto/genética , Dislipidemias/genética , Acantosis Nigricans/genética , Adulto , Edad de Inicio , Proteínas de Ciclo Celular/deficiencia , Simulación por Computador , Hiperinsulinismo Congénito/tratamiento farmacológico , Proteínas del Citoesqueleto/deficiencia , ADN Complementario/genética , Dislipidemias/tratamiento farmacológico , Exones/genética , Ácidos Grasos Insaturados/uso terapéutico , Femenino , Mutación del Sistema de Lectura , Heterocigoto , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Resistencia a la Insulina , Metformina/uso terapéutico , Persona de Mediana Edad , Linaje , Fenotipo , Plasmaféresis , Isoformas de Proteínas/genética , Síndrome , Transcripción GenéticaRESUMEN
We describe the second patient with the de novo p.Arg377Trp variant in ACTL6A (Actin-like 6A) (MIM#604958) and a phenotype reminiscent a disorder of the BRG1-associated factor (BAF) complex, including dysmorphic facies and acral malformations. So far, only three patients with ACTL6A variants and neurodevelopmental delay have been reported but the specific p.Arg377Trp mutation seems to correlate with a distinctive phenotype well-fitting a BAFopathy, which lacks in individuals carrying different mutations. This could suggest an emergent genotype-phenotype correlation among the ACTL6A-related phenotype.
Asunto(s)
Anomalías Múltiples/genética , Actinas/genética , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Deformidades Congénitas de la Mano/genética , Trastornos del Neurodesarrollo/genética , Anomalías Múltiples/patología , Niño , Deformidades Congénitas de la Mano/patología , Humanos , Masculino , Micrognatismo/patología , Trastornos del Neurodesarrollo/patologíaRESUMEN
A rare developmental delay (DD)/intellectual disability (ID) syndrome with craniofacial dysmorphisms and autistic features, termed White-Sutton syndrome (WHSUS, MIM#614787), has been recently described, identifying truncating mutations in the chromatin regulator POGZ (KIAA0461, MIM#614787). We describe a further WHSUS patient harboring a novel nonsense de novo POGZ variant, which afflicts a protein domain with transposase activity less frequently impacted by mutational events (DDE domain). This patient displays additional physical and behavioral features, these latter mimicking Smith-Magenis syndrome (SMS, MIM#182290). Considering sleep-wake cycle anomalies and abnormal behavior manifested by this boy, we reinforced the clinical resemblance between WHSUS and SMS, being both chromatinopathies. In addition, using the DeepGestalt technology, we identified a different facial overlap between WHSUS patients with mutations in the DDE domain (Group 1) and individuals harboring variants in other protein domains/regions (Group 2). This report further delineates the clinical and molecular repertoire of the POGZ-related phenotype, adding a novel patient with uncommon clinical and behavioral features and provides the first computer-aided facial study of WHSUS patients.
Asunto(s)
Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Síndrome de Smith-Magenis/genética , Transposasas/genética , Preescolar , Codón sin Sentido/genética , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/diagnóstico por imagen , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/fisiopatología , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/fisiopatología , Exoma/genética , Femenino , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/fisiopatología , Masculino , Mutación/genética , Fenotipo , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/diagnóstico por imagen , Síndrome de Smith-Magenis/fisiopatologíaRESUMEN
BACKGROUND: Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. CMM pathogenesis involves genetic and environmental factors. Recent studies have led to the identification of new genes involved in CMM susceptibility: beyond CDKN2A and CDK4, BAP1, POT1, and MITF were recently identified as potential high-risk melanoma susceptibility genes. OBJECTIVE: This study is aimed to evaluate the genetic predisposition to CMM in patients from central Italy. METHODS: From 1998 to 2017, genetic testing was performed in 888 cases with multiple primary melanoma and/or familial melanoma. Genetic analyses included the sequencing CDKN2A, CDK4, BAP1, POT1, and MITF in 202 cases, and of only CDKN2A and CDK4 codon 24 in 686 patients. By the evaluation of the personal and familial history, patients were divided in two clinical categories: "low significance" and "high significance" cases. RESULTS: 128 patients (72% belonging to the "high significance" category, 28% belonging to the "low significance" category) were found to carry a DNA change defined as pathogenic, likely pathogenic, variant of unknown significance (VUS)-favoring pathogenic or VUS. CONCLUSIONS: It is important to verify the genetic predisposition in CMM patients for an early diagnosis of further melanomas and/or other tumors associated with the characterized genotype.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Melanoma/genética , Melanoma/metabolismo , Adulto , Anciano , Quinasa 4 Dependiente de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Femenino , Humanos , Italia , Masculino , Factor de Transcripción Asociado a Microftalmía/genética , Persona de Mediana Edad , Estudios Retrospectivos , Complejo Shelterina , Proteínas de Unión a Telómeros/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/genéticaRESUMEN
Genetic syndromes are frequently associated with Intellectual Disability (ID), as well as craniofacial dysmorphisms. A group of ID syndromes with typical abnormal face related to chromatin remodeling defects, have been recognized, coining the term chromatinopathies. This is a molecular heterogeneous subset of congenital disorders caused by mutations of the various components of the Chromatin-Marking System (CMS), including modifiers of DNA and chromatin remodelers. We performed a phenotypic study on a sample of 120 individuals harboring variants in genes codifying for the histones enzymes, using the DeepGestalt technology. Three experiments (two multiclass comparison experiments and a frontal face-crop analysis) were conducted, analyzing respectively a total of 181 pediatric images in the first comparison experiment and 180 in the second, all individuals belonging predominantly to Caucasian population. The classification results were expressed in terms of the area under the curve (AUC) of the receiver-operating-characteristic curve (ROC). Significant values of AUC and low p-values were registered for all syndromes in the three experiments, in comparison with each other, with other ID syndromes characterized by recognizable craniofacial dysmorphisms and with unaffected controls. Final findings indicated that this group of diseases is characterized by distinctive dysmorphisms, which result pathognomonic. A correct interrogation and use of adequate informatics aids, could become a valid support for clinicians.
Asunto(s)
Facies , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Fenotipo , Niño , Preescolar , Estudios de Cohortes , Diagnóstico por Imagen , Femenino , Estudios de Asociación Genética/métodos , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Curva ROCRESUMEN
Mutations of SLC40A1 encoding ferroportin (Fpn), the unique cellular iron exporter, severely affect iron homeostasis causing type 4 hereditary hemochromatosis, an autosomal dominant iron overload condition with variable phenotypic manifestations. This disease can be classified as type 4A, better known as "ferroportin disease", which is due to "loss of function" mutations that lead to decreased iron export from cells, or as type 4B hemochromatosis, which is caused by "gain of function" mutations, conferring partial or complete resistance to hepcidin-mediated Fpn degradation. In this work, we discuss clinical and molecular findings on a group of patients in whom a SLC40A1 single copy missense variant was identified. Three novel variants, p.D181N, p.G204R and p.R296Q were functionally characterized. Fpn D181N and R296Q mutants can be classified as full or partial loss of function, respectively. Replacement of G204 with arginine appears to cause a more complex defect with impact both on iron export function and hepcidin sensitivity. This finding confirms the difficulty of predicting the effect of a mutation on the molecular properties of Fpn in order to provide an exhaustive explanation to the wide variability of the phenotype in type 4 hereditary hemochromatosis.
Asunto(s)
Proteínas de Transporte de Catión/deficiencia , Hemocromatosis/genética , Mutación , Adolescente , Adulto , Anciano , Proteínas de Transporte de Catión/genética , Niño , Salud de la Familia , Femenino , Ferritinas/metabolismo , Genes Dominantes , Estudios de Asociación Genética , Células HEK293 , Hepcidinas/química , Homeostasis , Humanos , Hierro/química , Italia , Masculino , Persona de Mediana Edad , Conformación Molecular , Mutación Missense , Fenotipo , Adulto JovenRESUMEN
Filamin A is an X-linked, ubiquitous actin-binding protein whose mutations are associated to multiple disorders with limited genotype-phenotype correlations. While gain-of-function mutations cause various bone dysplasias, loss-of-function variants are the most common cause of periventricular nodular heterotopias with variable soft connective tissue involvement, as well as X-linked cardiac valvular dystrophy (XCVD). The term "Ehlers-Danlos syndrome (EDS) with periventricular heterotopias" has been used in females with neurological, cardiovascular, integument and joint manifestations, but this nosology is still a matter of debate. We report the clinical and molecular update of an Italian family with an X-linked recessive soft connective tissue disorder and which was described, in 1975, as the first example of EDS type V of the Berlin nosology. The cutaneous phenotype of the index patient was close to classical EDS and all males died for a lethal cardiac valvular dystrophy. Whole exome sequencing identified the novel c.1829-1G>C splice variation in FLNA in two affected cousins. The nucleotide change was predicted to abolish the canonical splice acceptor site of exon 13 and to activate a cryptic acceptor site 15 bp downstream, leading to in frame deletion of five amino acid residues (p.Phe611_Gly615del). The predicted in frame deletion clusters with all the mutations previously identified in XCVD and falls within the N-terminus rod 1 domain of filamin A. Our findings expand the male-specific phenotype of FLNA mutations that now includes classical-like EDS with lethal cardiac valvular dystrophy, and offer further insights for the genotype-phenotype correlations within this spectrum. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Filaminas/genética , Mutación , Fenotipo , Sitios de Empalme de ARN , Niño , Preescolar , Exoma , Resultado Fatal , Femenino , Genes Ligados a X , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , LinajeRESUMEN
Although hyperferritinemia may be reflective of elevated total body iron stores, there are conditions in which ferritin levels are disproportionately elevated relative to iron status. Autosomal dominant forms of hyperferritinemia due to mutations in the L-ferritin IRE or in A helix of L-ferritin gene have been described, however cases of isolated hyperferritinemia still remain unsolved. We describe 12 Italian subjects with unexplained isolated hyperferritinemia (UIH). Four probands have affected siblings, but no affected parents or offspring. Sequencing analyses did not identify casual mutations in ferritin gene or IRE regions. These patients had normal levels of intracellular ferritin protein and mRNA in peripheral blood cells excluding pathological ferritin production at transcriptional and post-transcriptional level. In contrast with individuals with benign hyperferritinemia caused by mutations affecting the ferritin A helix, low rather than high glycosylation of serum ferritin was observed in our UIH subjects compared with controls. These findings suggest that subjects with UIH have a previously undescribed form of hyperferritinemia possibly attributable to increased cellular ferritin secretion and/or decreased serum ferritin clearance. The cause remains to be defined and we can only speculate the existence of mutations in gene/s not directly implicated in iron metabolism that could affect ferritin turnover including ferritin secretion.
Asunto(s)
Ferritinas/sangre , Trastornos del Metabolismo del Hierro/etiología , Adulto , Estudios de Casos y Controles , Femenino , Glicosilación , Humanos , Sobrecarga de Hierro , Italia , Masculino , Persona de Mediana Edad , Linaje , ARN Mensajero/sangre , Hermanos , Adulto JovenRESUMEN
Hereditary hemochromatosis (HH) is a heterogeneous disorder of iron metabolism. The most common form of the disease is Classic or type 1 HH, mainly caused by a biallelic missense p.Cys282Tyr (c.845G>A) mutation in the HFE gene. However, the penetrance of p.Cys282Tyr/p.Cys282Tyr genotype is incomplete in terms of both biochemical and clinical expressivity. Lack of penetrance is thought to be caused by several genetic and environmental factors. Recently, a lot of evidences on HH genetic modifiers were produced, often without conclusive results. We investigated 6 polymorphisms (rs10421768 in HAMP gene, rs235756 in BMP2 gene, rs2230267 in FTL gene, rs1439816 in SLC40A1 gene, rs41295942 in TFR2 gene and rs2111833 in TMPRSS6 gene) with uncertain function in order to further evaluate their role in an independent cohort of 109 HH type 1 patients. Our results make it likely the role of rs10421768, rs235756, rs2230267 and rs1439816 polymorphisms, respectively in HAMP, BMP2, FTL and SLC40A1 genes in HH expressivity. In addition, previous and our findings support a hypothetical multifactorial model of HH, characterized by a principal gene (HFE in HH type 1) and minor genetic and environmental factors that still have to be fully elucidated.
Asunto(s)
Apoferritinas/genética , Proteína Morfogenética Ósea 2/genética , Proteínas de Transporte de Catión/genética , Hemocromatosis/genética , Hepcidinas/genética , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de la Membrana/genética , Alelos , Femenino , Ferritinas/sangre , Frecuencia de los Genes , Interacción Gen-Ambiente , Genotipo , Hemocromatosis/sangre , Hemocromatosis/patología , Proteína de la Hemocromatosis , Humanos , Hierro/sangre , Masculino , Penetrancia , Fenotipo , Polimorfismo de Nucleótido Simple , Receptores de Transferrina/genética , Serina Endopeptidasas/genética , Transferrina/metabolismoRESUMEN
OBJECTIVE: Hereditary hemochromatosis (HH) is a common Mendelian disorder of iron metabolism. Eighty percent of northern Europeans descendant HH patients carry the same mutation (p.C282Y) in the HFE gene. Simultaneously, due to a founder effect, its frequency varies considerably between different populations. In Central-Southern Italy the prevalence of p.C282Y mutation is low and in several patients the disease has different causes. Four additional rarer forms have been described. Type 3 HH has been reported in about 50 families and no more than 30 TFR2 pathogenic mutations have been globally identified. The aim of this study is to assess the TFR2 role in non-HFE HH pathogenesis. STUDY DESIGN AND SETTING: TFR2 sequence analysis was performed on 45 Italian patients without HFE mutations. RESULTS: This study revealed TFR2 biallelic pathogenic mutations in 7/45 (15.6%) individuals. Moreover monoallelic TFR2 deleterious defects (18%) or polymorphisms with unclear meaning (36%) were identified. Besides, we recognized 10 novel variants and 9 described changes. CONCLUSION: We believe this to be the largest series of type 3 HH patients described so far. Present findings support the hypothesis of a main role of the TFR2 gene in HH pathogenesis in those regions, such as Central-Southern Italy, where the p.C282Y frequency is low.
Asunto(s)
Hemocromatosis/genética , Receptores de Transferrina/deficiencia , Alelos , Secuencia de Bases , Análisis Mutacional de ADN , Hemocromatosis/metabolismo , Hemocromatosis/patología , Humanos , Hierro/metabolismo , Sobrecarga de Hierro/genética , Sobrecarga de Hierro/metabolismo , Italia , Mutación , Receptores de Transferrina/genética , Receptores de Transferrina/metabolismoRESUMEN
Steroidogenic factor 1 (encoded by the NR5A1 gene) is a critical regulator of reproduction, controlling transcription of key genes involved in sexual dimorphism. To date, NR5A1 variants have been found in individuals with a 46,XY karyotype and gonadal dysgenesis, as well as with a wide spectrum of genital anomalies and, in some patients, with adrenal insufficiency. We describe evolution of gonadal function, from the neonatal period to puberty, in a patient with a 46,XY karyotype, a disorder of sexual development, and a mutation (c.691_699dupCTGCAGCTG) in the NR5A1 gene. The patient, ascertained at birth due to ambiguous genitalia, showed normal values of plasma testosterone in the late neonatal period. Evaluation of the hormonal profile over time indicated severe tubular testicular hypofunction suggestive for a 46,XY disorder of gonadal development. A comprehensive review of published reports of 46,XY and disordered sexual development related to the NR5A1 gene confirmed the clinical and hormonal variability in patients with NR5A1 mutations. Analysis of multiple data allowed us to define the most common features associated with NR5A1 mutations. We further confirmed the indication to perform NR5A1 screening in patients with 46,XY karyotype and disordered sexual development even when Müllerian structures appear to be absent and plasma testosterone levels are within the normal range for age.
Asunto(s)
Trastorno del Desarrollo Sexual 46,XY/sangre , Trastorno del Desarrollo Sexual 46,XY/genética , Hormonas/sangre , Mutación , Factor Esteroidogénico 1/genética , Niño , Análisis Mutacional de ADN , Trastorno del Desarrollo Sexual 46,XY/diagnóstico , Genitales Masculinos/anomalías , Disgenesia Gonadal 46 XY/diagnóstico , Disgenesia Gonadal 46 XY/genética , Disgenesia Gonadal 46 XY/patología , Humanos , Estudios Longitudinales , Masculino , FenotipoRESUMEN
Dilated cardiomyopathy (DCM) is defined as left ventricular enlargement accompanied by systolic dysfunction not explained by abnormal loading conditions or coronary heart disease. The DCM clinical spectrum is broad, ranging from subclinical to severe presentation with progression to end stage heart failure. To date, different genetic loci have been found to have moderate/definitive evidence for causality in DCM and pathogenic variants in the TTN gene represent the main genetic determinant. Here, we describe a family in which the co-occurrence of two genetic hits, one in the TTN and one in the BAG3 gene, was associated with heterogeneous clinical presentation ranging from subclinical phenotypes to acute cardiogenic shock mimicking fulminant myocarditis. We hypothesize that at least some specific BAG3 genotypes could be related to DCM presenting with acute heart failure and suggest that patients and relatives carrying BAG3 pathogenic variants should be addressed to a tertiary-level heart care center.
Asunto(s)
Cromosomas Humanos X/genética , Proteínas de Unión al ADN/genética , Dedos/anomalías , Enfermedades del Cabello/genética , Síndrome de Langer-Giedion/genética , Nariz/anomalías , Factores de Transcripción/genética , Adolescente , Deleción Cromosómica , Codón sin Sentido , Femenino , Humanos , Hallazgos Incidentales , Proteínas RepresorasRESUMEN
Constitutional heterozygous mutations in CHEK2 gene have been associated with hereditary cancer risk. To date, only a few homozygous CHEK2 mutations have been reported in families with cancer susceptibility. Here, we report two unrelated individuals with a personal and familial cancer history in whom biallelic CHEK2 alterations were identified. The first case resulted homozygous for the CHEK2 c.793-1 G > A (p.Asp265Thrfs*10) variant, and the second one was found to be compound heterozygous for the c.1100delC (p.Thr367Metfs*15) and the c.1312 G > T (p.Asp438Tyr) variants. Multiple cytogenetic anomalies were demonstrated on peripheral lymphocytes of both patients. A literature revision showed that a single other CHEK2 homozygous variant was previously associated to a constitutional randomly occurring multi-translocation karyotype from peripheral blood in humans. We hypothesize that, at least some biallelic CHEK2 mutations might be associated with a novel disorder, further expanding the group of chromosome instability syndromes. Additional studies on larger cohorts are needed to confirm if chromosomal instability could represent a marker for CHEK2 constitutionally mutated recessive genotypes, and to investigate the cancer risk and the occurrence of other anomalies typically observed in chromosome instability syndromes.