RESUMEN

The patient had clinical suspicion of THES. Complex genetic analyzes using WES, WGS were performed without success in the diagnosis. Further molecular analyzes using RNA and protein was necessary to reach the final correct THES diagnosis.

RESUMEN

Waardenburg syndrome (WS) is a common genetic cause of syndromic hearing loss, accounting for 2-5% of congenital cases. It is characterized by hearing impairment and pigmentation abnormalities in the skin, hair, and eyes. Seven genes are associated with WS: PAX3, MITF, EDNRB, EDN3, SOX10, KITLG, and SNAI2. This study investigates the genetic causes of WS in three familial cases. Whole-exome sequencing (WES) was performed to identify single nucleotide variants (SNVs). Copy number variants (CNVs) were analyzed from the WES raw data and through multiplex ligation-dependent probe amplification (MLPA). The study identified one pathogenic SNV and two novel CNVs, corresponding to type I and type II WS patterns in the three families. The SNV, a nonsense variant (c.1198C>T p.Arg400*), was found in MITF and segregated in the affected father. The two CNVs were a deletion of exon 5 in PAX3 in a family with two affected members and a large novel deletion comprising seven genes, including SOX10, in a family with three affected members. These findings confirmed a WS diagnosis through genetic testing. The study emphasizes the importance of integrating multiple genetic testing approaches for accurate and reliable diagnosis, highlighting their role in improving patient management and providing tailored genetic counseling.

RESUMEN

Background: Common variable immunodeficiency (CVID) is the most common symptomatic syndrome among inborn errors of immunity. Although several aspects of CVID immunopathology have been elucidated, predictive factors for mortality are incompletely defined. A genetic cause can be identified only in approximately 30% of patients. Objective: We sought to develop a mortality predictive score on the basis of the immunophenotypes and genotypes of patients with CVID. Methods: Twenty-one patients diagnosed with CVID in Córdoba, Argentina, were analyzed for clinical and laboratory data. Immunophenotyping was done by flow cytometry. CVID-associated mutations were identified by whole-exome sequencing. Results: Alive (15) and deceased (6) patients were compared. Univariate analysis showed significant differences in CD4+ T cells (P = .002), natural killer (NK) cells (P = .001), and memory switched B cells (P = .001) between groups. Logistic regression analysis showed a negative correlation between CD4+, NK, and memory switched B-cell counts and probability of survival over a 10-year period (CD4+ T cells: odds ratio [OR], 1.01; 95% CI, 1.001-1.020; NK cells: OR, 1.07; 95% CI, 1.02-1.17; and memory switched B cells: OR, 26.23; 95% CI, 2.06-2651.96). Receiver-operating characteristic curve analysis identified a survival cutoff point for each parameter (CD4+ T cells: 546 cells/mL; AUC, 0.87; sensitivity, 60%; specificity, 100%; memory switched B cells: 0.84 cells/mL; AUC, 0.92; sensitivity, 100%; specificity, 85%; and NK cells: 45 cells/mL; AUC, 0.92; sensitivity, 83%; specificity, 100%). Genetic analysis on 14 (9 female and 5 male) patients from the cohort revealed mutations associated with inborn errors of immunity in 6 patients. Conclusions: A score to predict mortality is proposed on the basis of CD4+ T, NK, and memory switched B-cell counts in patients with CVID.

RESUMEN

Primary congenital glaucoma (PCG) is one of the leading causes of visual damage and blindness, severely affecting the quality of life of affected children. It is characterized by cupping of the optic disc and loss of ganglion cells due to elevated intraocular pressure. While most PCG patients exhibit epiphora, photophobia, and buphthalmos with corneal opacity, variability in phenotypic manifestations is not uncommon. Prompt diagnosis and treatment of PCG affected individuals becomes relevant to preserve visual function throughout their lives. Most PCG cases are sporadic or autosomal recessive; however, an incompletely dominant autosomal dominant form arising from mutations in the TEK gene has recently been demonstrated. Here, we describe the clinical and mutational features of a cohort of Mexican patients with TEK-related PCG. Our results support the involvement of the TEK gene as an important cause of the disease in our ethnic group and expand the mutational spectrum causing PCG by reporting 10 novel disease-causing variants.

Asunto(s)

Glaucoma , Mutación , Linaje , Fenotipo , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Estudios de Cohortes , Análisis Mutacional de ADN , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Glaucoma/genética , Glaucoma/patología , Glaucoma/congénito , México/epidemiología , Mutación/genética

RESUMEN

B-cell acute lymphoblastic leukemia (B-ALL) is one of the most common childhood cancers worldwide. Although most cases are sporadic, some familial forms, inherited as autosomal dominant traits with incomplete penetrance, have been described over the last few years. Germline pathogenic variants in transcription factors such as PAX5, IKZF1, and ETV6 have been identified as causal in familial forms. The proband was a 7-year-old Mexican girl diagnosed with high-risk B-ALL at five years and 11 months of age. Family history showed that the proband's mother had high-risk B-ALL at 16 months of age. She received chemotherapy and was discharged at nine years of age without any evidence of recurrence of leukemia. The proband's father was outside the family nucleus, but no history of leukemia or cancer was present up to the last contact with the mother. We performed exome sequencing on the proband and the proband's mother and identified the PAX5 variant NM_016734.3:c.963del: p.(Ala322LeufsTer11), located in the transactivation domain of the PAX5 protein. The variant was classified as probably pathogenic according to the ACMG criteria. To the best of our knowledge, this is the first Mexican family with an inherited increased risk of childhood B-ALL caused by a novel germline pathogenic variant of PAX5. Identifying individuals with a hereditary predisposition to cancer is essential for modern oncological practice. Individuals at high risk of leukemia would benefit from hematopoietic stem cell transplantation, but family members carrying the pathogenic variant should be excluded as hematopoietic stem cell donors.

RESUMEN

Baker-Gordon Syndrome (BAGOS) is a genetically determined 4 (NDD), represented by a phenotypic spectrum of moderate to severe intellectual disability, resulting from mutations in the synaptotagmin 1 (SYT1) gene. Its prevalence is estimated at 1:1,000,000 and the known gene variants have indicated complete penetrance with variable expressivity. SYT1 is a membrane trafficking protein in presynaptic vesicles, which exerts a complex influence on synaptic transmission, with fundamental roles in the release of neurotransmitters and facilitators of endocytosis, impacting both neurotransmission and neuron plasticity. The current case report describes the first Brazilian male patient diagnosed at 17-year-old, and the 39th reported case globally using whole-exome sequencing. A de novo heterozygous missense mutation at chr12q:79448958 (NM_005639.2; c.1103T>C; p.Ile368Thr) in the SYT1 was found and classified as a pathogenic variant. The proband's clinical phenotype was compatible with BAGOS, involving behavioral changes such as irritability and severe intellectual disability. Knowledge about the mechanism of action and the extent of the genotypic and phenotypic presentations of the mutations in the SYT1 is still unfolding. Thus, we aimed to describe additional genotype-phenotype correlation for BAGOS, contributing to the expansion of the existing knowledge of such a heterogeneous ultra-rare syndrome, and, therefore, improve its diagnostic yield, case management, and therapeutic journey for future patients.

RESUMEN

Early onset myopathies are a clinically and histologically heterogeneous monogenic diseases linked to approximately 90 genes. Molecular diagnosis is challenging, especially in patients with a mild phenotype. We describe a 26-year-old man with neonatal hypotonia, motor delay and seizures during infancy, and non-progressive, mild muscular weakness in adulthood. Serum Creatine kinase level was normal. Whole-body muscle MRI showed thin muscles, and brain MRI was unremarkable. A deltoid muscle biopsy showed glycogen storage. WGS revealed a de novo 1.4 Mb-deletion of chromosome 14, confirmed by Array-CGH. This microdeletion causes the loss of ten genes including RALGAPA1, encoding for RalA, a regulator of glucose transporter 4 (GLUT4) expression at the membrane of myofibers. GLUT4 was overexpressed in patient's muscle. Here we highlight the importance to search for chromosomal alterations in the diagnostic workup of early onset myopathies.

Asunto(s)

Glucógeno , Enfermedades Musculares , Masculino , Recién Nacido , Humanos , Adulto , Cromosomas Humanos Par 14 , Enfermedades Musculares/genética , Hipotonía Muscular/genética , Fenotipo , Proteínas del Tejido Nervioso/genética , Proteínas Activadoras de GTPasa/genética

RESUMEN

Lamellar ichthyosis (LI) is an autosomal recessive congenital ichthyosis characterized by generalized dry skin and severe scaling. It is caused by biallelic mutations in the TGM1 gene, however molecular data from non-Caucasian populations are limited. Results of genetic-molecular analysis of a group of LI pedigrees originating from two close small populations from south Mexico are presented. LI affected individuals belonging to 9 apparently unrelated families were studied. Exome sequencing or Sanger sequencing in probands from each family was carried out. Furthermore, DNA from 294 unaffected subjects from one of the communities were Sanger sequenced to determine the carrier frequency of the c.427C > T TGM1 variant. Five different TGM1 pathogenic variants, either in homozygous or in compound heterozygous state, were demonstrated in affected subjects. The two most common variants were c.427C > T (p.Arg143Cys) and c.1159+1G > T. A novel c.1645+1G > T TGM1 pathogenic allele was recognized. Carrier frequency analysis identified a total of 23 individuals heterozygous for the c.427C > T variant, predicting a prevalence of 78 carriers per 1000 inhabitants in the community. A high TGM1 allelic heterogeneity with 5 different LI-causing alleles in a limited geographic area was demonstrated. While the occurrence of homozygosity for a founder mutation is expected in small populations with high frequency of a particular autosomal recessive disorder, the occurrence of multiple pathogenic alleles has been previously described, a situation known as the Reúnion paradox. Our results expand the current knowledge of the mutational spectrum of TGM1-linked LI.

RESUMEN

Objective: Bipolar disorder is a heritable chronic mental disorder that causes psychosocial impairment through depressive/manic episodes. Familial transmission of bipolar disorder does not follow simple Mendelian patterns of inheritance. The aim of this study was to describe a large family with 12 members affected by bipolar disorder. Whole-exome sequencing was performed for eight members, three of whom were diagnosed with bipolar disorder, and another reported as "borderline." Methods: Whole-exome sequencing data allowed us to select variants that the affected members had in common, including and excluding the "borderline" individual with moderate anxiety and obsessive-compulsive traits. Results: The results favored designating certain genes as predispositional to bipolar disorder: a heterozygous missense variant in CLN6 resulted in a "borderline" phenotype that, if combined with a heterozygous missense variant in ZNF92, is responsible for the more severe bipolar disorder phenotype. Both rare missense changes are predicted to disrupt protein function. Conclusions: Loss of both alleles in CLN6 causes neuronal ceroid lipofuscinosis, a severe progressive childhood neurological disorder. Our results indicate that heterozygous CLN6 carriers, previously reported as healthy, may be susceptible to bipolar disorder later in life if associated with additional variants in ZNF92.

RESUMEN

OBJECTIVE: Bipolar disorder is a heritable chronic mental disorder that causes psychosocial impairment through depressive/manic episodes. Familial transmission of bipolar disorder does not follow simple Mendelian patterns of inheritance. The aim of this study was to describe a large family with 12 members affected by bipolar disorder. Whole-exome sequencing was performed for eight members, three of whom were diagnosed with bipolar disorder, and another reported as "borderline." METHODS: Whole-exome sequencing data allowed us to select variants that the affected members had in common, including and excluding the "borderline" individual with moderate anxiety and obsessive-compulsive traits. RESULTS: The results favored designating certain genes as predispositional to bipolar disorder: a heterozygous missense variant in CLN6 resulted in a "borderline" phenotype that, if combined with a heterozygous missense variant in ZNF92, is responsible for the more severe bipolar disorder phenotype. Both rare missense changes are predicted to disrupt protein function. CONCLUSIONS: Loss of both alleles in CLN6 causes neuronal ceroid lipofuscinosis, a severe progressive childhood neurological disorder. Our results indicate that heterozygous CLN6 carriers, previously reported as healthy, may be susceptible to bipolar disorder later in life if associated with additional variants in ZNF92.

Asunto(s)

Trastorno Bipolar , Lipofuscinosis Ceroideas Neuronales , Humanos , Proteínas de la Membrana/genética , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Lipofuscinosis Ceroideas Neuronales/genética

RESUMEN

Introduction: The transcription factor Nuclear factor of activated T cells 5 (NFAT5), pivotal in immune regulation and function, can be induced by osmotic stress and tonicity-independent signals. Objective: We aimed to investigate and characterize two unrelated patients with Epstein-Barr virus susceptibility and no known genetic etiology. Methods: After informed consent, we reviewed the electronic charts, extracted genomic DNA, performed whole-exome sequencing, filtered, and prioritized their variants, and confirmed through Sanger sequencing, family segregation analysis, and some functional assays, including lymphoproliferation, cytotoxicity, and characterization of natural killer cells. Results: We describe two cases of pediatric Mexican patients with rare heterozygous missense variants in NFAT5 and EBV susceptibility, a school-age girl with chronic-active infection of the liver and bowel, and a teenage boy who died of hemophagocytic lymphohistiocytosis. Discussion: NFAT5 is an important regulator of the immune response. NFAT5 haploinsufficiency has been described as an immunodeficiency syndrome affecting both innate and adaptive immunity. EBV susceptibility might be another manifestation in the spectrum of this disease.

Asunto(s)

Infecciones por Virus de Epstein-Barr , Linfohistiocitosis Hemofagocítica , Adolescente , Niño , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Femenino , Haploinsuficiencia , Herpesvirus Humano 4 , Humanos , Masculino , Factores de Transcripción/genética

Asunto(s)

Pruebas Genéticas , Trastornos del Movimiento , Humanos , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/genética , Mutación , Secuenciación del Exoma

RESUMEN

Despite having a favorable response to platinum-based chemotherapies, ~15% of Testicular Germ-Cell Tumor (TGCT) patients are platinum-resistant. Mortality rates among Latin American countries have remained constant over time, which makes the study of this population of particular interest. To gain insight into this phenomenon, we conducted whole-exome sequencing, microarray-based comparative genomic hybridization, and copy number analysis of 32 tumors from a Mexican cohort, of which 18 were platinum-sensitive and 14 were platinum-resistant. We incorporated analyses of mutational burden, driver mutations, and SNV and CNV signatures. DNA breakpoints in genes were also investigated and might represent an interesting research opportunity. We observed that sensitivity to chemotherapy does not seem to be explained by any of the mutations detected. Instead, we uncovered CNVs, particularly amplifications on segment 2q11.1 as a novel variant with chemosensitivity biomarker potential. Our data shed light into understanding platinum resistance in a Latin-origin population.

RESUMEN

In this work, we aimed to provide the genetic diagnosis of a large cohort of patients affected with inherited retinal dystrophies (IRDs) from Mexico. Our data add valuable information to the genetic portrait in rare ocular diseases of Mesoamerican populations, which are mostly under-represented in genetic studies. A cohort of 144 unrelated probands with a clinical diagnosis of IRD were analyzed by next-generation sequencing using target gene panels (overall including 346 genes and 65 intronic sequences). Four unsolved cases were analyzed by whole-exome sequencing (WES). The pathogenicity of new variants was assessed by in silico prediction algorithms and classified following the American College of Medical Genetics and Genomics (ACMG) guidelines. Pathogenic or likely pathogenic variants were identified in 105 probands, with a final diagnostic yield of 72.9%; 17 cases (11.8%) were partially solved. Eighteen patients were clinically reclassified after a genetic diagnostic test (17.1%). In our Mexican cohort, mutations in 48 genes were found, with ABCA4, CRB1, RPGR and USH2A as the major contributors. Notably, over 50 new putatively pathogenic variants were identified. Our data highlight cases with relevant clinical and genetic features due to mutations in the RAB28 and CWC27 genes, enrich the novel mutation repertoire and expand the IRD landscape of the Mexican population.

Asunto(s)

Heterogeneidad Genética , Fenotipo , Enfermedades de la Retina/genética , Adulto , Femenino , Humanos , Masculino , México , Mutación , Enfermedades de la Retina/patología

RESUMEN

Cerebellofaciodental syndrome is characterized by facial dysmorphisms, intellectual disability, cerebellar hypoplasia, and dental anomalies. It is an autosomal-recessive condition described in 2015 caused by pathogenic variants in BRF1. Here, we report a Brazilian patient who faced a diagnostic challenge beginning at 11 months of age. Fortunately, whole-exome sequencing (WES) was performed, detecting the BRF1 variants NM_001519.3:c.1649delG:p.(Gly550Alafs*36) and c.421C>T:p.(Arg141Cys) in compound heterozygosity, thus finally achieving a diagnosis of cerebellofaciodental syndrome. The patient is currently 25 years old and is the oldest patient yet reported. The clinical report and a review of published cases are presented. Atlanto-occipital fusion, a reduced foramen magnum and basilar invagination leading to compression of the medulla-spinal cord transition are skeletal findings not reported in previous cases. The description of syndromes with dental findings shows that such anomalies can be an important clue to relevant differential diagnoses. The cooperation of groups from different international centers made possible the resolution of this and other cases and is one of the strategies to bring medical advances to developing countries, where many patients with rare diseases are difficult to diagnose definitively.

Asunto(s)

Anomalías Múltiples/genética , Cerebelo/anomalías , Anomalías Craneofaciales/genética , Discapacidad Intelectual/genética , Atrofia Muscular/genética , Malformaciones del Sistema Nervioso/genética , Factores Asociados con la Proteína de Unión a TATA/genética , Anomalías Dentarias/genética , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/fisiopatología , Adulto , Brasil/epidemiología , Cerebelo/diagnóstico por imagen , Cerebelo/fisiopatología , Niño , Preescolar , Anomalías Craneofaciales/diagnóstico por imagen , Anomalías Craneofaciales/fisiopatología , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/fisiopatología , Masculino , Atrofia Muscular/diagnóstico por imagen , Atrofia Muscular/fisiopatología , Malformaciones del Sistema Nervioso/diagnóstico por imagen , Malformaciones del Sistema Nervioso/fisiopatología , Anomalías Dentarias/diagnóstico por imagen , Anomalías Dentarias/fisiopatología , Secuenciación del Exoma

RESUMEN

Triple-negative breast cancer (TNBC) presents a marked diversity at the molecular level, which promotes a clinical heterogeneity that further complicates treatment. We performed a detailed whole exome sequencing profile of 29 Mexican patients with long follow-up TNBC to identify genomic alterations associated with overall survival (OS), disease-free survival (DFS), and pathologic complete response (PCR), with the aim to define their role as molecular predictive factors of treatment response and prognosis. We detected 31 driver genes with pathogenic mutations in TP53 (53%), BRCA1/2 (27%), CDKN1B (9%), PIK3CA (9%), and PTEN (9%), and 16 operative mutational signatures. Moreover, tumors with mutations in BRCA1/2 showed a trend of sensitivity to platinum salts. We found an association between deficiency in DNA repair and surveillance genes and DFS. Across all analyzed tumors we consistently found a heterogeneous molecular complexity in terms of allelic composition and operative mutational processes, which hampered the definition of molecular traits with clinical utility. This work contributes to the elucidation of the global molecular alterations of TNBC by providing accurate genomic data that may help forthcoming studies to improve treatment and survival. This is the first study that integrates genomic alterations with a long follow-up of clinical variables in a Latin American population that is an underrepresented ethnicity in most of the genomic studies.

Asunto(s)

Mutación , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/mortalidad , Adulto , Anciano , Trastornos por Deficiencias en la Reparación del ADN/genética , Femenino , Humanos , Estimación de Kaplan-Meier , Linfocitos Infiltrantes de Tumor/patología , Persona de Mediana Edad , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Secuenciación del Exoma

RESUMEN

BACKGROUND: Preeclampsia (PE) is a frequently occurring multisystemic disease affecting ~5% of pregnancies. PE patients may develop HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet), a mother and foetus life-threatening condition. Research into HELLP's genetic origin has been relatively unsuccessful, mainly because normal placental function and blood pressure regulation involve the fine-regulation of hundreds of genes. OBJECTIVE: To identify new genes and mutations constituting potential biomarkers for HELLP syndrome. STUDY DESIGN: The present case-control study involved whole-exome sequencing of 79 unrelated HELLP women. Candidate variants were screened in a control population constituted by 176 individuals. Stringent bioinformatics filters were used for selecting potentially etiological sequence variants in a subset of 487 genes. We used robust in silico mutation modelling for predicting the potential effect on protein structure. RESULTS: We identified numerous sequence variants in genes related to angiogenesis/coagulation/blood pressure regulation, cell differentiation/communication/adhesion, cell cycle and transcriptional gene regulation, extracellular matrix biology, lipid metabolism and immunological response. Five sequence variants generated premature stop codons in genes playing an essential role in placental physiology (STOX1, PDGFD, IGF2, MMP1 and DNAH11). Six variants (ERAP1- p.Ile915Thr, ERAP2- p.Leu837Ser, COMT-p.His192Gln, CSAD-p.Pro418Ser, CDH1- p.Ala298Thr and CCR2-p.Met249Lys) led to destabilisation of protein structure as they had significant energy and residue interaction-related changes. We identified at least two mutations in 57% of patients, arguing in favour of a polygenic origin for the HELLP syndrome. CONCLUSION: Our results provide novel evidence regarding PE/HELLP's genetic origin, leading to new biomarkers, having potential clinical usefulness, being proposed.

Asunto(s)

Secuenciación del Exoma/métodos , Síndrome HELLP/genética , Estudios de Casos y Controles , Femenino , Marcadores Genéticos , Síndrome HELLP/sangre , Humanos , Embarazo

RESUMEN

SPG11 mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to SPG11 mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3 T MRI scan. Mean age and disease duration were 29 and 13.2 years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. SPG11-related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration.

Asunto(s)

Ganglios Basales/diagnóstico por imagen , Mutación , Proteínas/genética , Paraplejía Espástica Hereditaria/genética , Sustancia Blanca/diagnóstico por imagen , Adolescente , Adulto , Imagen de Difusión Tensora , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Pruebas Neuropsicológicas , Paraplejía Espástica Hereditaria/diagnóstico por imagen , Adulto Joven

RESUMEN

Splicing-related gene mutations might affect the expression of a single gene or multiple genes and cause clinically heterogeneous diseases. With the advent of next-generation sequencing, several splicing gene mutations have been exposed, yet most major spliceosome genes have no reports of germline mutations and therefore, their effects are largely unknown. We describe the previously unreported concurrence of intellectual disability, short stature, poor speech, and minor craniofacial and hand anomalies in 2 female siblings with 3 homozygous missense variants in SNRPA (a component of the U1 small nuclear ribonucleoprotein complex) characterized by homozygosity mapping and whole exome sequencing. Combined, c.97A>G, c.98T>C, and c.100T>A, in exon 2 of SNRPA lead to p.Ile33Ala and p.Phe34Ile exchanges, which were predicted in silico to be deleterious. Although both patients exhibited some clinical features seen in other spliceosomal disorders, their complete clinical phenotype appears to be rather uncommon, a finding that may further support the notion that mutations in components of the major spliceosome do not strictly lead to the same syndromes/phenotypes.

Asunto(s)

Secuenciación del Exoma , Discapacidad Intelectual/genética , Mutación Missense/genética , Ribonucleoproteína Nuclear Pequeña U1/genética , Hermanos , Adulto , Niño , Preescolar , Exoma/genética , Femenino , Homocigoto , Humanos , Recién Nacido , Síndrome , Adulto Joven

RESUMEN

BACKGROUND: Mucopolysaccharidosis IIIB (MPS IIIB) is a genetic disease characterized by mutations in the NAGLU gene, deficiency of α-N-acetylglucosaminidase, multiple congenital malformations and an increased susceptibility to malignancy. Because of the slow progressive nature of this disease and its atypical symptoms, the misdiagnosis of MPS IIIB is not rare in clinical practice. This misdiagnosis could be avoided by using next-generation sequencing (NGS) techniques, which have been shown to have superior performance for detecting mutations underlying rare inherited disorders in previous studies. CASE PRESENTATION: Whole exome sequencing (WES) was conducted and the putative pathogenic variants were validated by Sanger sequencing. The activity of MPS IIIB related enzyme in the patient's blood serum was assayed. A heterozygous, non-synonymous mutation (c.1562C>T, p.P521L) as well as a novel mutation (c.1705C>A, p.Q569K) were found in the NAGLU gene of the patient. The two mutations were validated by Sanger sequencing. Our data showed that this patient's c.1562C>T, p.P521L mutation in the NAGLU gene was inherited from his father and c.1705C>A, p.Q569K was from his mother. The diagnosis was further confirmed by an enzymatic activity assay after patient recall and follow-up. CONCLUSIONS: Our results describe an atypical form of MPS IIIB and illustrate the diagnostic potential of targeted WES in Mendelian disease with unknown etiology. WES could become a powerful tool for molecular diagnosis of MPS IIIB in clinical setting.

Asunto(s)

Acetilglucosaminidasa/genética , Exoma/genética , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mucopolisacaridosis III/genética , Mutación/genética , Niño , Análisis Mutacional de ADN , Humanos , Iduronidasa/genética , Masculino , Pronóstico