RESUMEN
Charcot-Marie-Tooth disease (CMT) rarely presents with painful symptoms, which mainly occur in association with myelin protein zero (MPZ) gene mutations. We aimed to further characterize the features of painful neuropathic phenotypes in MPZ-related CMT. We report on a 58-year-old woman with a longstanding history of intermittent migrant pain and dysesthesias. Examination showed minimal clinical signs of neuropathy along with mild changes upon electroneurographic examination, consistent with an intermediate pattern, and small-fiber loss upon skin biopsy. Genetic testing identified the heterozygous variant p.Trp101Ter in MPZ. We identified another 20 CMT patients in the literature who presented with neuropathic pain as a main feature in association with MPZ mutations, mostly in the extracellular MPZ domain; the majority of these patients showed late onset (14/20), with motor-nerve-conduction velocities predominantly in the intermediate range (12/20). It is hypothesized that some MPZ mutations could manifest with, or predispose to, neuropathic pain. However, the mechanisms linking MPZ mutations and pain-generating nerve changes are unclear, as are the possible role of modifier factors. This peculiar CMT presentation may be diagnostically misleading, as it is suggestive of an acquired pain syndrome rather than of an inherited neuropathy.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth , Neuralgia , Neuropatía de Fibras Pequeñas , Femenino , Humanos , Persona de Mediana Edad , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/genética , Proteína P0 de la Mielina/genética , Mutación , Pruebas Genéticas , Neuralgia/etiología , Neuralgia/genética , Neuropatía de Fibras Pequeñas/genéticaRESUMEN
Neurofibromatosis type I, a genetic condition due to pathogenic variants in the NF1 gene, is burdened by a high rate of complications, including neoplasms, which increase morbidity and mortality for the disease. We retrospectively re-evaluated the NF1 gene variants found in the period 2000-2019 and we studied for genotype/phenotype correlations of disease complications and neoplasms 34 variants, which were shared by at least two unrelated families (range 2-11) for a total 141 of probands and 21 relatives affected by Neurofibromatosis type I. Recurrent variants could be ascribed to the most common mutational mechanisms (C to T transition, microsatellite slippage, non-homologous recombination). In genotype/phenotype correlations, the variants p.Arg440*, p.Tyr489Cys, and p.Arg1947*, together with the gross gene deletions, displayed the highest rates of complications. When considering neoplasms, carriers of variants falling in the extradomain region at the 5' end of NF1 had a lower age-related cancer frequency than the rest of the gene sequence, showing a borderline significance (p = 0.045), which was not conserved after correction with covariates. We conclude that (1) hotspots in NF1 occur via different mutational mechanisms, (2) several variants are associated with high rates of complications and cancers, and (3) there is an initial evidence toward a lower cancer risk for carriers of variants in the 5' end of the NF1 gene although not significant at the multivariate analysis.
Asunto(s)
Genes de Neurofibromatosis 1 , Neurofibromatosis 1/genética , Neurofibromina 1/genética , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Mutación , Neoplasias/genética , Fenotipo , Estudios RetrospectivosRESUMEN
The prevalence of Beckwith-Wiedemann spectrum (BWSp) is tenfold increased in children conceived through assisted reproductive techniques (ART). More than 90% of ART-BWSp patients reported so far display imprinting center 2 loss-of-methylations (IC2-LoM), versus 50% of naturally conceived BWSp patients. We describe a cohort of 74 ART-BWSp patients comparing their features with a cohort of naturally conceived BWSp patients, with the ART-BWSp patients previously described in literature, and with the general population of children born from ART. We found that the distribution of UPD(11)pat was not significantly different in ART and naturally conceived patients. We observed 68.9% of IC2-LoM and 16.2% of mosaic UPD(11)pat in our ART cohort, that strongly differ from the figure reported in other cohorts so far. Since UPD(11)pat likely results from post-fertilization recombination events, our findings allows to hypothesize that more complex molecular mechanisms, besides methylation disturbances, may underlie BWSp increased risk in ART pregnancies. Moreover, comparing the clinical features of ART and non-ART BWSp patients, we found that ART-BWSp patients might have a milder phenotype. Finally, our data show a progressive increase in the prevalence of BWSp over time, paralleling that of ART usage in the last decades.
Asunto(s)
Síndrome de Beckwith-Wiedemann , Impresión Genómica , Síndrome de Beckwith-Wiedemann/epidemiología , Síndrome de Beckwith-Wiedemann/genética , Metilación de ADN/genética , Femenino , Fertilización , Impresión Genómica/genética , Humanos , Embarazo , Técnicas Reproductivas Asistidas/efectos adversosRESUMEN
Neurofibromatosis type I, a genetic disorder due to mutations in the NF1 gene, is characterized by a high mutation rate (about 50% of the cases are de novo) but, with the exception of whole gene deletions associated with a more severe phenotype, no specific hotspots and few solid genotype/phenotype correlations. After retrospectively re-evaluating all NF1 gene variants found in the diagnostic activity, we studied 108 patients affected by neurofibromatosis type I who harbored mutations that had not been previously reported in the international databases, with the aim of analyzing their type and distribution along the gene and of correlating them with the phenotypic features of the affected patients. Out of the 108 previously unreported variants, 14 were inherited by one of the affected parents and 94 were de novo. Twenty-nine (26.9%) mutations were of uncertain significance, whereas 79 (73.2%) were predicted as pathogenic or probably pathogenic. No differential distribution in the exons or in the protein domains was observed and no statistically significant genotype/phenotype correlation was found, confirming previous evidences.
Asunto(s)
Estudios de Asociación Genética , Mutación , Neurofibromatosis 1/genética , Neurofibromina 1/genética , Adulto , Alelos , Genes de Neurofibromatosis 1 , Genotipo , Humanos , FenotipoRESUMEN
Variations of DNA sequences in the human genome range from large, microscopically visible chromosome anomalies to single nucleotide changes. Submicroscopic genomic copy number variations, i.e. chromosomal imbalances which are undetectable by conventional cytogenetic analysis, play an intriguing clinical role. In this study, we describe the clinical consequences of the concurrent presence of an interstitial deletion in 13q34 and a terminal deletion in 4q35.2 in an Italian family. The index patient, a 19-year-old male, as well as his 12-year-old sister are carriers of both deletions, one of maternal and the other of paternal origin. The phenotype includes language delay, multiorgan involvement and bleeding diathesis with mild deficiency of factors X and VII. In the sister, the concomitant presence of Noonan syndrome may partly explain the clinical symptoms. The deleted region on chromosome 13 involves several genes (ATP11A, MCF2L, F7, F10, PROZ, PCID2, CUL4A, and LAMP1); some of these seem to play a role in the proband's phenotype. The terminal deletion in 4q35.2 contains other OMIM genes (FRG1, FRG2 and DBET); moreover, the 4q region is reported as a susceptibility locus for Crohn's disease, diagnosed in the proband's father. To our knowledge, this is the first report of a family with these 2 submicroscopic copy number changes. We tried to relate the clinical phenotype of the proband and his family to the molecular function of the involved genes.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 13 , Cromosomas Humanos Par 4 , Deficiencia del Factor VII/genética , Deficiencia del Factor X/genética , Trastornos Hemorrágicos/genética , Síndrome de Noonan/genética , Niño , Bandeo Cromosómico , Variaciones en el Número de Copia de ADN , Deficiencia del Factor VII/patología , Deficiencia del Factor X/patología , Femenino , Trastornos Hemorrágicos/patología , Humanos , Hibridación Fluorescente in Situ , Patrón de Herencia , Italia , Masculino , Síndrome de Noonan/patología , Linaje , Fenotipo , Adulto JovenRESUMEN
Leucine zipper-like transcription regulator 1 (LZTR1) acts as a negative factor that suppresses RAS function and MAPK signaling; mutations in this protein may dysregulate RAS ubiquitination and lead to impaired degradation of RAS superfamily proteins. Germline LZTR1 variants are reported in Noonan syndrome, either autosomal dominant or autosomal recessive, and in susceptibility to schwannomatosis. This article explores the genetic and phenotypic diversity of the autosomal dominant LZTR1-related disorders, compiling a cohort of previously published patients (51 with the Noonan phenotype and 123 with schwannomatosis) and presenting two additional adult-onset cases: a male with schwannomatosis and Parkinson's disease and a female with Noonan syndrome, generalized joint hypermobility, and breast cancer. This review confirms that autosomal dominant LZTR1-related disorders exhibit an extreme phenotypic variability, ranging from relatively mild manifestations to severe and multi-systemic involvement, and offers updated frequences of each clinical feature. The aim is to precisely define the clinical spectrum of LZTR1-related diseases, using also two new emblematic clinical cases. Gaining insight into the mechanisms underneath this variability is crucial to achieve precision diagnostics and the development of therapeutic interventions.
Asunto(s)
Neurilemoma , Síndrome de Noonan , Fenotipo , Humanos , Masculino , Femenino , Síndrome de Noonan/genética , Síndrome de Noonan/patología , Adulto , Neurilemoma/genética , Neurilemoma/patología , Neurofibromatosis/genética , Neurofibromatosis/patología , Transactivadores/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Edad de Inicio , Factores de Transcripción/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Persona de Mediana Edad , Genes Dominantes , MutaciónRESUMEN
Mosaic chromosomal anomalies arising in the product of conception and the final fetal chromosomal arrangement are expression of complex biological mechanisms. The rescue of unbalanced chromosome with selection of the most viable cell line/s in the embryo and the unfavourable imbalances in placental tissues was documented in our previous paper and in the literature. We report four additional cases with mosaic derivative chromosomes in different feto-placental tissues, further showing the instability of an intermediate gross imbalance as a frequent mechanism of de novo cryptic deletions and duplications. In conclusion we underline how the extensive remodeling of unbalanced chromosomes in placental tissues represents the 'backstage' of de novo structural rearrangements, as the early phases of a long selection process that the genome undergo during embryogenesis.
RESUMEN
Germline variants occurring in BRCA1 and BRCA2 give rise to hereditary breast and ovarian cancer (HBOC) syndrome, predisposing to breast, ovarian, fallopian tube, and peritoneal cancers marked by elevated incidences of genomic aberrations that correspond to poor prognoses. These genes are in fact involved in genetic integrity, particularly in the process of homologous recombination (HR) DNA repair, a high-fidelity repair system for mending DNA double-strand breaks. In addition to its implication in HBOC pathogenesis, the impairment of HR has become a prime target for therapeutic intervention utilizing poly (ADP-ribose) polymerase (PARP) inhibitors. In the present review, we introduce the molecular roles of HR orchestrated by BRCA1 and BRCA2 within the framework of sensitivity to PARP inhibitors. We examine the genetic architecture underneath breast and ovarian cancer ranging from high- and mid- to low-penetrant predisposing genes and taking into account both germline and somatic variations. Finally, we consider higher levels of complexity of the genomic landscape such as polygenic risk scores and other approaches aiming to optimize therapeutic and preventive strategies for breast and ovarian cancer.
Asunto(s)
Genes BRCA2 , Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Reparación del ADN por Recombinación , Roturas del ADN de Doble Cadena , Poli(ADP-Ribosa) Polimerasas/genéticaRESUMEN
The finding of variants of uncertain significance (VUS) in the activity of a diagnostic genetic laboratory is a common issue, which is however provisional and needs to be periodically re-evaluated, due to the continuous advancements in our knowledge of the genetic diseases. Neurofibromatosis type 1, caused by the occurrence of heterozygous pathogenic NF1 variants, is a good model for studying the evolution of VUS, due to the widespread use of genetic testing for the disease, the constant enrichment of the international databases with NF1 variants and the full adult penetrance of the disease, which makes genotyping the parents a crucial step in the diagnostic workflow. The present study retrospectively reviewed and reinterpreted the genetic test results of NF1 in a diagnostic genetic laboratory in the period from January 1, 2000 to December 31, 2020. All the VUS were reinterpreted using the 2015 consensus standards and guidelines for the interpretation. Out of 589 NF1 genetic tests which were performed in the period, a total of 85 VUS were found and reinterpreted in 72 cases (84.7%): 21 (29.2%) were reclassified as benign/likely benign, whereas 51 (70.8%) were recoded as pathogenic/likely pathogenic with a significant trend distribution (Chi square test for trend p = 0.005). Synonymous VUS have mainly been reclassified as class 1 and 2 (7/8, 87.5%), whereas missense variants have been attributed to class 4 and 5 in 38 out of the 58 cases (65.5%). These findings underline an improvement in the classification of variants over time, suggesting that a reinterpretation of the genetic tests should be routinely performed to support the physicians in the clinical diagnosis of genetic diseases.
Asunto(s)
Predisposición Genética a la Enfermedad , Neurofibromatosis 1 , Adulto , Humanos , Neurofibromatosis 1/diagnóstico , Neurofibromatosis 1/genética , Estudios Retrospectivos , Pruebas Genéticas/métodos , Mutación MissenseRESUMEN
Novel approaches to uncover the molecular etiology of neurodevelopmental disorders (NDD) are highly needed. Even using a powerful tool such as whole exome sequencing (WES), the diagnostic process may still prove long and arduous due to the high clinical and genetic heterogeneity of these conditions. The main strategies to improve the diagnostic rate are based on family segregation, re-evaluation of the clinical features by reverse-phenotyping, re-analysis of unsolved NGS-based cases and epigenetic functional studies. In this article, we described three selected cases from a cohort of patients with NDD in which trio WES was applied, in order to underline the typical challenges encountered during the diagnostic process: (1) an ultra-rare condition caused by a missense variant in MEIS2, identified through the updated Solve-RD re-analysis; (2) a patient with Noonan-like features in which the NGS analysis revealed a novel variant in NIPBL causing Cornelia de Lange syndrome; and (3) a case with de novo variants in genes involved in the chromatin-remodeling complex, for which the study of the epigenetic signature excluded a pathogenic role. In this perspective, we aimed to (i) provide an example of the relevance of the genetic re-analysis of all unsolved cases through network projects on rare diseases; (ii) point out the role and the uncertainties of the reverse phenotyping in the interpretation of the genetic results; and (iii) describe the use of methylation signatures in neurodevelopmental syndromes for the validation of the variants of uncertain significance.
Asunto(s)
Síndrome de Cornelia de Lange , Enfermedades no Diagnosticadas , Humanos , Secuenciación del Exoma , Enfermedades no Diagnosticadas/genética , Pruebas Genéticas , Síndrome de Cornelia de Lange/genética , Mutación Missense , Factores de Transcripción/genética , Enfermedades Raras/genética , Proteínas de Ciclo Celular/genéticaRESUMEN
Retinitis pigmentosa (RP) is the most common inherited retinal disease (IRD) and is characterized by photoreceptor degeneration and progressive vision loss. We report 4 patients presenting with RP from 3 unrelated families with variants in TBC1D32, which to date has never been associated with an IRD. To validate TBC1D32 as a putative RP causative gene, we combined Xenopus in vivo approaches and human induced pluripotent stem cell-derived (iPSC-derived) retinal models. Our data showed that TBC1D32 was expressed during retinal development and that it played an important role in retinal pigment epithelium (RPE) differentiation. Furthermore, we identified a role for TBC1D32 in ciliogenesis of the RPE. We demonstrated elongated ciliary defects that resulted in disrupted apical tight junctions, loss of functionality (delayed retinoid cycling and altered secretion balance), and the onset of an epithelial-mesenchymal transition-like phenotype. Last, our results suggested photoreceptor differentiation defects, including connecting cilium anomalies, that resulted in impaired trafficking to the outer segment in cones and rods in TBC1D32 iPSC-derived retinal organoids. Overall, our data highlight a critical role for TBC1D32 in the retina and demonstrate that TBC1D32 mutations lead to RP. We thus identify TBC1D32 as an IRD-causative gene.
Asunto(s)
Células Madre Pluripotentes Inducidas , Degeneración Retiniana , Retinitis Pigmentosa , Humanos , Retina , Retinitis Pigmentosa/genética , Degeneración Retiniana/genética , Epitelio Pigmentado de la Retina , Proteínas Adaptadoras Transductoras de SeñalesRESUMEN
AIMS: Brugada syndrome (BrS) is an inherited arrhythmic disease characterized by a coved ST-segment elevation in the right precordial electrocardiogram leads (type 1 ECG pattern) and is associated with a risk of malignant ventricular arrhythmias and sudden cardiac death. In order to assess the predictive value of the Shanghai Score System for the presence of a SCN5A mutation in clinical practice, we studied a cohort of 125 patients with spontaneous or fever/drug-induced BrS type 1 ECG pattern, variably associated with symptoms and a positive family history. METHODS: The Shanghai Score System items were collected for each patient and PR and QRS complex intervals were measured. Patients were genotyped through a next-generation sequencing (NGS) custom panel for the presence of SCN5A mutations and the common SCN5A polymorphism (H558R). RESULTS: The total Shanghai Score was higher in SCN5A+ patients than in SCN5A- patients. The 81% of SCN5A+ patients and the 100% of patients with a SCN5A truncating variant exhibit a spontaneous type 1 ECG pattern. A significant increase in PR (Pâ=â0.006) and QRS (Pâ=â0.02) was detected in the SCN5A+ group. The presence of the common H558R polymorphism did not significantly correlate with any of the items of the Shanghai Score, nor with the total score of the system. CONCLUSION: Data from our study suggest the usefulness of Shanghai Score collection in clinical practice in order to maximize genetic test appropriateness. Our data further highlight SCN5A mutations as a cause of conduction impairment in BrS patients.
Asunto(s)
Síndrome de Brugada , Humanos , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , China/epidemiología , Canal de Sodio Activado por Voltaje NAV1.5/genética , Arritmias Cardíacas , Mutación , ElectrocardiografíaRESUMEN
Background: Hypertrophic cardiomyopathy is an autosomal dominant disease. The main feature of this disorder is its occurrence in patients who present a left ventricular hypertrophy, unexplained by the loading conditions, usually asymmetric with greatest involvement most commonly of the interventricular septum.Case presentation During a sports medicine control, a ultrasound scan in a 17 years old patient has shown a concentric left ventricular parietal hypertrophy associated with a 23 mm mid- basal interventricular septum thickness. After genetic counselling, a positive family history for hypertrophic cardiac disease and parents' consanguineity was found. The genetic basis of the hypertrophic cardiomyopathy was investigated through a dedicated gene panel. The genetic test has revealed the presence of the variant c.3424G>A (p.Glu1142Lys) in the MYH7 gene in a homozygous state. Genotyping of the parents and of the two brothers revealed the presence of the MYH7 variant in heterozygosity in both parents and in the younger brother. In all of them, variable signs of hypertrophic cardiomyopathy were found. Conclusions: Our findings report the presence of a homozygous variant in a sarcomeric gene (MYH7) which gave rise to early HCM, whereas the variant in a heterozygous state was associated to much milder cardiac phenotypes in the affected relatives. The onset and the progression of the hypertrophic cardiomyopathy in the reported family is to be referred to the presence of the variant in hetero- or homo-zygosity in a gene dosage manner.
RESUMEN
The finding of USP9X variants in females has been associated with female-restricted X-linked mental retardation (MRXS99F), a rare syndrome featured by developmental delay and distinct congenital anomalies. Here, we report a female fetus with MRXS99F due to a novel frameshift variant, c.6679_6685delAAATTATinsTCCTG (p.Lys2227SerfsTer2) in USP9X, which was present in a mosaic state in the amniocytes and in the peripheral blood after birth (14% and 30%, respectively). The X methylation status analysis displayed a partially skewed X-inactivation with 80% of inactive paternal X. The first signs of the MRXS99F were prenatally detected at 20 weeks, with an enlarged posterior cranial fossa, an upward rotation of the cerebellar vermis and partial corpus callosum agenesis, together with a cardiac septal defect and a single umbilical artery. After birth and during postnatal follow-up the anal anteriorization and the presence of a bilateral membranous choanal atresia were noted, whereas the MRI revealed the hypo/aplasia of the olfactory bulbs, a widening of the subarachnoid spaces and a delay in the myelinisation. During the 18-months follow-up a severe growth and global developmental delay, together with a bilateral moderate deafness with a threshold at 40 dB, dental enamel erosions and an initial scoliosis were observed. We report the prenatal and postnatal features of a classical MRXS99F phenotype and a mosaic USP9X frameshift variant with a partially skewed X inactivation and discuss genotype/phenotype correlations in view of the published studies so far.
Asunto(s)
Agenesia del Cuerpo Calloso , Atresia de las Coanas , Femenino , Humanos , Embarazo , Agenesia del Cuerpo Calloso/genética , Mutación del Sistema de Lectura , Fenotipo , Síndrome , Ubiquitina Tiolesterasa/genéticaRESUMEN
Alport syndrome (ATS) is a nephropathy characterized by the association of progressive hematuric nephritis with ultrastructural changes of the glomerular basement membrane (thinning, thickening, and splitting), sensorineural deafness, and variable ocular abnormalities (anterior lenticonus, macular flecks, and cataracts). The most common mode of transmission is X-linked inheritance, due to COL4A5 mutations. X-linked ATS is rarely associated with diffuse leiomyomatosis (DL), a benign hypertrophy of the visceral smooth muscle in gastrointestinal, respiratory, and female reproductive tracts. The ATS-DL complex is due to deletions that encompass the 5' ends of the COL4A5 and COL4A6 genes and include the bidirectional promoter. In this paper, we described 3 ATS-DL cases, 2 familial and 1 sporadic bearing a deletion encompassing the 5'-end of both the COL4A5 and COL4A6 genes, as identified by multiplex ligation-dependent probe amplification (MLPA) analysis. The array-CGH technique allowed a better definition of deletion size, confirming that the proximal breakpoint was within COL4A6 intron 2 in 2 cases. Surprisingly, 1 case had a deletion extending proximally beyond exon 3 of COL4A6, as confirmed by qPCR analysis. This is the largest deletion reported to date that has been associated with ATS-DL and this case should lead us to reconsider the mechanisms that might be involved in the development of diffuse leiomyomatosis.
Asunto(s)
Secuencia de Bases/genética , Colágeno Tipo IV/genética , Eliminación de Secuencia/genética , Adulto , Niño , Hibridación Genómica Comparativa , Femenino , Humanos , Intrones/genética , Leiomiomatosis , Masculino , Datos de Secuencia Molecular , Nefritis Hereditaria/genética , Linaje , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto JovenRESUMEN
Women with pathogenic germline mutations in BRCA1 and BRCA2 genes have an increased risk to develop breast and ovarian cancer. There is, however, a high interpersonal variability in the modality and timing of tumor onset in those subjects, thus suggesting a potential role of other individual's genetic, epigenetic, and environmental risk factors in modulating the penetrance of BRCA mutations. MicroRNAs (miRNAs) are small noncoding RNAs that can modulate the expression of several genes involved in cancer initiation and progression. MiRNAs are dysregulated at all stages of breast cancer and although they are accessible and evaluable, a standardized method for miRNA assessment is needed to ensure comparable data analysis and accuracy of results. The aim of this review was to highlight the role of miRNAs as potential biological markers for BRCA mutation carriers. In particular, biological and clinical implications of a link between lifestyle and nutritional modifiable factors, miRNA expression and germline BRCA1 and BRCA2 mutations are discussed with the knowledge of the best available scientific evidence.
RESUMEN
BACKGROUND: Alport syndrome (ATS) is a hereditary progressive hematuric nephropathy associated with sensorineural deafness and ocular abnormalities, which is caused by mutations in the COL4A5 gene (X-linked ATS) and in two autosomal genes, COL4A4 and COL4A3, responsible of both recessive ATS and, when present in heterozygosity, of a spectrum of phenotypes ranging from isolated hematuria to frank renal disease. METHODS: Retrospective analysis of the clinical and genetic features of 76 patients from 34 unrelated ATS families (11 with mutations in COL4A5, 11 in COL4A3, and 12 in COL4A4) and genotype/phenotype correlation for the COL4A3/COL4A4 heterozygotes (34 patients from 14 families). RESULTS: Eight (24%) of the 34 heterozygous COL4A3 and COL4A4 carriers developed renal failure at a mean age of 57 years, with a significantly lower risk than hemizygous COL4A5 or double heterozygous COL4A3/COL4A4 carriers (p < 0.01), but not different from that of the heterozygous COL4A5 females (p = 0.6). Heterozygous carriers of frameshift/splicing variants in COL4A3/COL4A4 presented a higher risk of developing renal failure than those with missense variants in the glycine domains (p = 0.015). CONCLUSION: The renal functional prognosis of patients with COL4A3/COL4A4-positive ATS recapitulates that of the X-linked ATS forms, with differences between heterozygous vs. double heterozygous patients and between carriers of loss-of-function vs. missense variants.
Asunto(s)
Colágeno Tipo IV/genética , Genotipo , Nefritis Hereditaria/genética , Fenotipo , Adolescente , Adulto , Anciano , Niño , Femenino , Heterocigoto , Humanos , Mutación con Pérdida de Función , Masculino , Persona de Mediana Edad , Mutación Missense , Nefritis Hereditaria/patologíaRESUMEN
BACKGROUND: Alport syndrome is a clinically and genetically heterogeneous nephropathy characterized by glomerular basement membrane lesions often associated with hearing loss and ocular anomalies. While the X-linked and the autosomal recessive forms are well known, the autosomal dominant form is not well acknowledged. METHODS: We have clinically investigated 38 patients with a diagnosis of autosomal dominant Alport syndrome belonging to eight different families. The analysis of the COL4A4 gene was performed by denaturing high performance liquid chromatography and automated DNA sequencing. RESULTS: In our cohort of patients, only 24.3% (9/37) reached end-stage renal disease, at the mean age of 51.2 years. Four patients had hearing loss (13.3%) and none ocular changes. Molecular analysis revealed eight novel private COL4A4 gene mutations: three frameshift, three missense and two splice-site mutations. CONCLUSIONS: These data indicate autosomal dominant Alport syndrome as a disease with a low risk of ocular and hearing anomalies but with a significant risk to develop renal failure although at an older age than the X-linked form. We were unable to demonstrate a genotype-phenotype correlation. Altogether, these data make difficult the differential diagnosis with the benign familial haematuria due to heterozygous mutations of COL4A4 and COL4A3, especially in young patients, and with the X-linked form of Alport syndrome in families where only females are affected. A correct diagnosis and prognosis is based on a comprehensive clinical investigation in as many family members as possible associated with a broadly formal genetic analysis of the pedigree.
Asunto(s)
Colágeno Tipo IV/genética , Mutación/genética , Nefritis Hereditaria/diagnóstico , Nefritis Hereditaria/genética , Anciano , Diagnóstico Diferencial , Femenino , Mutación del Sistema de Lectura/genética , Hematuria/diagnóstico , Hematuria/genética , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Linaje , Polimorfismo Genético/genética , PronósticoRESUMEN
Microduplications of the X chromosome are a rare cause of X-linked intellectual disability (XLID), a clinically and genetically heterogeneous spectrum of disorders. In the present study, a 950-kb Xp22.12 microduplication including the RPS6KA3 gene was detected in affected members of a family, including the proband (male), his mother and one maternal uncle. Four female carriers had major depression and one of them also had mild intellectual disability. The present and previous cases with overlapping microduplications suggest that Xp22.12 microduplications can be included in the neuropsychiatric copy number variations.