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1.
Int J Mol Sci ; 25(17)2024 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-39273623

RESUMEN

The etiology of neurodevelopmental disorders and epilepsy is very heterogeneous and partly still unknown, and the research of causative genes related to these diseases is still in progress. In 2020, pathogenic variants of the TET3 gene were associated with Beck-Fahrner syndrome, which is characterized by neurodevelopmental delay, intellectual and learning disabilities of variable degree, growth abnormalities, hypotonia and seizures. Variants of TET3 have been described having both an autosomal dominant with a milder phenotype and an autosomal recessive pattern. To date, in the literature, only 28 patients are reported with pathogenic variants of the TET3 gene, and only 9 of them have epilepsy. We describe a 31-year-old woman with macrocephaly, mild neurodevelopmental delay and a long history of epilepsy. Trio-based exome sequencing identified a de novo heterozygous TET3 variant, c.2867G>A p.(Arg956Gln), never described before, absent in the general population and predicted to be potentially pathogenetic by bioinformatics tools. This report aims to describe the clinical history of our patient, the pharmacological treatment and clinical response, as well as the biological characteristics of this new variant.


Asunto(s)
Epilepsia , Megalencefalia , Mutación Missense , Humanos , Femenino , Adulto , Epilepsia/genética , Megalencefalia/genética , Dioxigenasas/genética , Proteínas de Unión al ADN/genética , Secuenciación del Exoma , Fenotipo
2.
Am J Med Genet A ; 185(4): 1204-1210, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33442900

RESUMEN

Feingold Syndrome type 1 (FS1) is an autosomal dominant disorder due to a loss of function mutations in the MYCN gene. FS1 is generally clinically characterized by mild learning disability, microcephaly, short palpebral fissures, short stature, brachymesophalangy, hypoplastic thumbs, as well as syndactyly of toes, variably associated with organ abnormalities, the most common being gastrointestinal atresia. In current literature, more than 120 FS1 patients have been described, but diagnostic criteria are not well agreed upon, likewise the genotype-phenotype correlations are not well understood. Here, we describe 11 FS1 patients, belonging to six distinct families, where we have identified three novel MYCN mutations along with three pathogenetic variants, the latter which have already been reported. Several patients presented a mild phenotype of the condition and they have been diagnosed as being affected only after segregation analyses of the MYCN mutation identified in the propositus. We also describe here the first ever FS1 patient with severe intellectual disability having a maternally inherited MYCN variant together with an additional GNAO1 mutation inherited paternally. Mutations in the GNAO1 gene are associated with a specific form of intellectual disability and epilepsy, thus the finding of two different rare diseases in the same patient could explain his severe phenotype. Therein, a thorough investigation is merited into the possibility that additional variants in patients with a MYCN mutation and severe phenotype do exist. Finally, in order to guarantee a more reliable diagnosis of FS1, we suggest using both major and minor clinical-molecular diagnostic criteria.


Asunto(s)
Párpados/anomalías , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/genética , Deformidades Congénitas de las Extremidades/genética , Microcefalia/genética , Proteína Proto-Oncogénica N-Myc/genética , Fístula Traqueoesofágica/genética , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Adolescente , Niño , Preescolar , Párpados/patología , Femenino , Estudios de Asociación Genética , Pruebas Genéticas , Genotipo , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/patología , Deformidades Congénitas de las Extremidades/complicaciones , Deformidades Congénitas de las Extremidades/patología , Masculino , Microcefalia/complicaciones , Microcefalia/patología , Fenotipo , Sindactilia/complicaciones , Sindactilia/genética , Sindactilia/patología , Fístula Traqueoesofágica/complicaciones , Fístula Traqueoesofágica/patología
3.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-34445317

RESUMEN

The 22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder in humans and is the result of a recurrent 1.5 to 2.5 Mb deletion, encompassing approximately 20-40 genes, respectively. The clinical presentation of the typical deletion includes: Velocardiofacial, Di George, Opitz G/BBB and Conotruncalanomaly face syndromes. Atypical deletions (proximal, distal or nested) are rare and characterized mainly by normal phenotype or mild intellectual disability and variable clinical features. The pathogenetic mechanisms underlying this disorder are not completely understood. Because the 22q11.2 region harbours genes coding for transcriptional factors and chromatin remodelers, in this study, we performed analysis of genome-wide DNA methylation of peripheral blood from 49 patients with 22q11.2DS using the Illumina Infinium Methylation EPIC bead chip arrays. This cohort comprises 43 typical, 2 proximal and 4 distal deletions. We demonstrated the evidence of a unique and highly specific episignature in all typical and proximal 22q11.2DS. The sensitivity and specificity of this signature was further confirmed by comparing it to over 1500 patients with other neurodevelopmental disorders with known episignatures. Mapping the 22q11.2DS DNA methylation episignature provides both novel insights into the molecular pathogenesis of this disorder and an effective tool in the molecular diagnosis of 22q11.2DS.


Asunto(s)
Metilación de ADN , Síndrome de DiGeorge/genética , Epigenoma , Femenino , Humanos , Lactante , Masculino
4.
Am J Med Genet A ; 182(10): 2377-2383, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32744787

RESUMEN

Mutations in the MBOAT7 gene have been described in 43 patients, belonging to 18 families, showing nonspecific clinical features (intellectual disability [ID], seizures, microcephaly or macrocephaly, and mild to moderate cerebellar atrophy) that make the clinical diagnosis difficult. Here we report the first Italian patient, a 22.5-year-old female, one of the oldest reported, born to apparently consanguineous parents. She shows severe ID, macrocephaly, seizures, aggressive outbursts, hyperphagia. We also documented progressive atrophy of the cerebellar vermis, that appeared not before the age of 7. The whole-exome sequencing of the trio identified a novel homozygous variant c.1057_1058delGCinsCA (p.Ala353His) in the MBOAT7 gene. The variant is considered to be likely pathogenic, since it is absent from population database and it lies in a highly conserved amino acid residue. This disorder has a neurometabolic pathogenesis, implicating a phospholipid remodeling abnormalities. A brain hydrogen-magnetic resonance spectroscopy (H-MRS) examination in our patient disclosed a peculiar neurometabolic profile in the cerebellar hemispheric region. This new finding could address the clinical suspicion of MBOAT7-related disorder, among the wide range of genetic conditions associated with ID and cerebellar atrophy. Moreover, the documented progression of cerebellar atrophy and the worsening of the disease only after some years open to the possibility of a therapeutic window after birth.


Asunto(s)
Aciltransferasas/genética , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Atrofias Olivopontocerebelosas/genética , Adolescente , Adulto , Cerebelo/diagnóstico por imagen , Niño , Consanguinidad , Exoma/genética , Femenino , Homocigoto , Humanos , Discapacidad Intelectual/patología , Masculino , Atrofias Olivopontocerebelosas/patología , Linaje , Secuenciación del Exoma , Adulto Joven
5.
Int J Mol Sci ; 19(10)2018 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-30332768

RESUMEN

Sotos syndrome is one of the most common overgrowth diseases and it predisposes patients to cancer, generally in childhood. The prevalence of this genetic disorder is 1:10,000⁻1:50,000, and it is characterized by wide allelic heterogeneity, with more than 100 different known mutations in the nuclear receptor-binding SET domain containing protein 1 (NSD1) gene. Most of these alterations are deletions and common micro-deletions with haploinsufficiency. Singular variants are missense mutations. The present study reports a case of a 4-year-old boy with specific clinical features of Sotos syndrome and a particular complex skin hamartoma on the right femoral side, in addition to other minor findings, such as a "café-au-lait" spot on the right hemithorax and syndactyly of the second and third right toes. NSD1 gene analysis identified a de novo missense mutation, "c.[5867T>A]+[=]"; "p.[Leu1956Gln]+[=]", that was not previously described in the literature. This mutation was localized to the functional domain of the gene and was likely the cause of Sotos syndrome in our patient. We also compared aspects of our patient's condition with the clinical features of tuberous sclerosis (TSC), which is an autosomal neurocutaneous syndrome caused by mutations in the TSC1/TSC2 genes. These genes control cell growth and cell survival. This disorder is characterized by hamartomas in multiple organ systems, several coetaneous abnormalities, epilepsy, and increased risk of several types of tumors.


Asunto(s)
Hamartoma/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación Missense/genética , Proteínas Nucleares/genética , Piel/patología , Síndrome de Sotos/genética , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Preescolar , Dermoscopía , Femenino , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Masculino , Proteínas Nucleares/química , Linaje
6.
Int J Mol Sci ; 18(9)2017 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-28926972

RESUMEN

Moyamoya angiopathy (MA) is a rare cerebrovascular disorder characterised by the progressive occlusion of the internal carotid artery. Its aetiology is uncertain, but a genetic background seems likely, given the high MA familial rate. To investigate the aetiology of craniosynostosis and juvenile moyamoya in a 14-year-old male patient, we performed an array-comparative genomic hybridisation revealing a de novo interstitial deletion of 8.5 Mb in chromosome region 1p32p31. The deletion involved 34 protein coding genes, including NF1A, whose haploinsufficiency is indicated as being mainly responsible for the 1p32-p31 chromosome deletion syndrome phenotype (OMIM 613735). Our patient also has a deleted FOXD3 of the FOX gene family of transcription factors, which plays an important role in neural crest cell growth and differentiation. As the murine FOXD3-/- model shows craniofacial anomalies and abnormal common carotid artery morphology, it can be hypothesised that FOXD3 is involved in the pathogenesis of the craniofacial and vascular defects observed in our patient. In support of our assumption, we found in the literature another patient with a syndromic form of MA who had a deletion involving another FOX gene (FOXC1). In addition to describing the clinical history of our patient, we have reviewed all of the available literature concerning other patients with a 1p32p31 deletion, including cases from the Decipher database, and we have also reviewed the genetic disorders associated with MA, which is a useful guide for the diagnosis of syndromic form of MA.


Asunto(s)
Trastornos de los Cromosomas/genética , Craneosinostosis/genética , Enfermedad de Moyamoya/genética , Adolescente , Deleción Cromosómica , Trastornos de los Cromosomas/diagnóstico , Cromosomas Humanos Par 1/genética , Craneosinostosis/diagnóstico , Factores de Transcripción Forkhead/genética , Factor Nuclear 1-alfa del Hepatocito/genética , Humanos , Masculino , Enfermedad de Moyamoya/diagnóstico , Síndrome
7.
Am J Med Genet A ; 170(9): 2377-82, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27312080

RESUMEN

Mutations of the MED12 gene have been reported mainly in males with FG (Opitz-Kaveggia), Lujan-Fryns, or X-linked Ohdo syndromes. Recently, a different phenotype characterized by minor anomalies, severe intellectual disability (ID), and absent language was reported in female and male patients belonging to the same family and carrying a frameshift MED12 mutation (c.5898dupC). Here, we report on two brothers and their niece affected by severe and mild ID, respectively, where whole exome sequencing combined with variant analysis within a panel of ID-related genes, disclosed a novel c.2312T>C (p.Ile771Thr) MED12 mutation. This variant, which has not been reported as a polymorphism, was not present in a third unaffected brother, and was predicted to be deleterious by five bioinformatic databases. This finding together with the phenotypic analogies shared with the carriers of c.5898dupC mutation suggests the existence of a fourth MED12-related disorder, characterized by severe ID, absent or deficient language and, milder, clinical manifestation in heterozygotes. We have reviewed the literature on MED12 heterozygotes, their clinical manifestations, and discuss the possible biological causes of this condition. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Estudios de Asociación Genética , Complejo Mediador/genética , Mutación , Fenotipo , Adulto , Anciano , Alelos , Secuencia de Aminoácidos , Encéfalo/patología , Hibridación Genómica Comparativa , Facies , Femenino , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Mutación Missense
8.
Neurogenetics ; 15(4): 237-42, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25129042

RESUMEN

Gilles de la Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor and vocal tics, frequently associated with psychiatric co-morbidities. Despite the significant level of heritability, the genetic architecture of TS still remains elusive. Herein, we investigated an Italian family where an 8-year-old boy, his father, and paternal uncle have a diagnosis of TS. Array-CGH and high resolution SNP-array analyses revealed a heterozygous microdeletion of ∼135 kb at the 7q36.2 locus in the proband and his father. Fluorescent in situ hybridization and quantitative PCR (qPCR) analyses confirmed the presence of the alteration also in the paternal uncle. The deletion selectively involves the first exon of the DPP6 gene, leading to a down-regulation of its expression, as demonstrated by the reduced messenger RNA (mRNA) levels assessed by RT-qPCR. The DPP6 gene encodes for a type II membrane glycoprotein expressed predominantly in the central nervous system. To date, a de novo DPP6 exonic duplication, of uncertain significance, was reported in one patient with TS. Moreover, the DPP6 gene has been implicated in the pathogenesis of autism spectrum disorder (ASD) and, notably, in haloperidol-induced dyskinesia. This first familial case provides evidence for association between DPP6 haploinsufficiency and TS, further suggesting a plausible molecular link between TS and ASD, and might shed some light on the efficacy and tolerability profiles of antidopaminergic agents used for tic management, thus prompting further studies on a larger cohort of patients.


Asunto(s)
Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Eliminación de Gen , Haploinsuficiencia , Proteínas del Tejido Nervioso/genética , Canales de Potasio/genética , Síndrome de Tourette/genética , Adulto , Anciano , Niño , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Exones , Familia , Salud de la Familia , Humanos , Masculino , Proteínas del Tejido Nervioso/metabolismo , Linaje , Polimorfismo de Nucleótido Simple , Canales de Potasio/metabolismo , ARN Mensajero/metabolismo
9.
Am J Med Genet A ; 164A(12): 3137-41, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25257502

RESUMEN

The most frequent causes of Intellectual Disability (ID)/Autism Spectrum Disorders (ASDs) are chromosomal abnormalities, genomic rearrangements and submicroscopic deletions coupled with duplications. We report here on an 11-year-old girl showing autism, macrocephaly, and facial dysmorphism, in which array-CGH showed a de novo microdeletion of ∼114 Kb in the 14q11.2 chromosomal region, involving the SUPT16H, CHD8, and RAB2B genes. Four patients with ID and/or ASD and/or macrocephaly with overlapping deletions have been previously described: three showed very large rearrangements (>1 Mb), while one had a microdeletion of ∼101 Kb, largely overlapping the one reported herein. The minimal critical region, considering present and previous cases, contains the SUPT16H and CHD8 genes. Notably, recent studies also disclosed CHD8 heterozygous loss-of-function mutations in patients with ASD and macrocephaly. Our finding shows the presence of a recurrent microdeletion associated with a clinically recognizable phenotype, and further on underlines the pivotal role of CHD8 gene in the pathogenesis of the disorder.


Asunto(s)
Trastorno Autístico/genética , Trastorno Autístico/patología , Deleción Cromosómica , Cromosomas Humanos Par 14/genética , Proteínas de Unión al ADN/genética , Megalencefalia/genética , Megalencefalia/patología , Factores de Transcripción/genética , Niño , Hibridación Genómica Comparativa , Femenino , Humanos
10.
Am J Med Genet A ; 158A(9): 2091-9, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22821852

RESUMEN

Nablus mask-like facial syndrome (NMLFS) has many distinctive phenotypic features, particularly tight glistening skin with reduced facial expression, blepharophimosis, telecanthus, bulky nasal tip, abnormal external ear architecture, upswept frontal hairline, and sparse eyebrows. Over the last few years, several individuals with NMLFS have been reported to have a microdeletion of 8q21.3q22.1, demonstrated by microarray analysis. The minimal overlapping region is 93.98-96.22 Mb (hg19). Here we present clinical and microarray data from five singletons and two mother-child pairs who have heterozygous deletions significantly overlapping the region associated with NMLFS. Notably, while one mother and child were said to have mild tightening of facial skin, none of these individuals exhibited reduced facial expression or the classical facial phenotype of NMLFS. These findings indicate that deletion of the 8q21.3q22.1 region is necessary but not sufficient for development of the NMLFS. We discuss possible genetic mechanisms underlying the complex pattern of inheritance for this condition.


Asunto(s)
Anomalías Múltiples/genética , Blefarofimosis/genética , Deleción Cromosómica , Cromosomas Humanos Par 8 , Anomalías Craneofaciales/genética , Adolescente , Adulto , Preescolar , Femenino , Humanos , Masculino , Fenotipo
11.
Am J Med Genet A ; 155A(5): 1106-8, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21465646

RESUMEN

Craniotubular dysplasias (CTD) are a heterogeneous group of genetic disorders of skeletal development, whose clinical and etiological classification is still much debated. One of the most common form is the autosomal dominant craniometaphyseal dysplasia (CMD) which is associated with mutation in the ANKH gene. In the literature a few families are reported with CMD phenotype that suggest an autosomal recessive (AR) pattern of inheritance. A candidate locus at 6q21-22 has been mapped in a large inbred Brazilian family, but the gene of the recessive form is still unknown. Our data on a female patient with CMD phenotype, born from healthy first degree cousins and displaying homozygosity for polymorphic markers at the 6q21-22 locus, further support the existence of an AR CMD, expanding its clinical spectrum to a more severe phenotype.


Asunto(s)
Enfermedades del Desarrollo Óseo , Cromosomas Humanos Par 6 , Parálisis Facial , Homocigoto , Osteoporosis , Enfermedades del Desarrollo Óseo/genética , Mapeo Cromosómico , Trastornos Craneomandibulares , Parálisis Facial/genética , Femenino , Humanos , Osteoporosis/genética , Cráneo/anomalías
12.
Am J Med Genet A ; 155A(10): 2473-8, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21910216

RESUMEN

We report on a 9-year-old female patient with facial anomalies and developmental delay, heterozygous for three de novo rearrangements: a paracentric inversion of chromosome 7, an apparently balanced translocation between chromosome 1 and 7, involving the same inverted chromosome 7, detected by standard cytogenetic analysis [46,XX, der(7) inv(7)(q21.1q32.1)t(1;7)(q23q32.1)]; and a 2p16.1 deletion, spanning about 3.5 Mb of genomic DNA, shown by SNP-array analysis [arr 2p16.1 (56,706,666-60,234,485)x1 dn]. Clinical features and cytogenetic imbalance in our patient were similar to those reported in five published cases, suggesting that this genomic region is prone to recombination and its hemizygosity results in a distinct although variable spectrum of clinical manifestations.


Asunto(s)
Anomalías Múltiples/patología , Deleción Cromosómica , Cromosomas Humanos Par 2/genética , Discapacidades del Desarrollo/patología , Anomalías Múltiples/genética , Niño , Inversión Cromosómica/genética , Discapacidades del Desarrollo/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Polimorfismo de Nucleótido Simple/genética , Síndrome , Translocación Genética/genética
13.
Genes (Basel) ; 12(9)2021 09 12.
Artículo en Inglés | MEDLINE | ID: mdl-34573388

RESUMEN

In recent years, a rare form of autosomal recessive brachyolmia associated with amelogenesis imperfecta (AI) has been described as a novel nosologic entity. This disorder is characterized by skeletal dysplasia (e.g., platyspondyly, short trunk, scoliosis, broad ilia, elongated femoral necks with coxa valga) and severe enamel and dental anomalies. Pathogenic variants in the latent transforming growth factor-ß binding protein 3 (LTBP3) gene have been found implicated in the pathogenesis of this disorder. So far, biallelic pathogenic LTBP3 variants have been identified in less than 10 families. We here report a young boy born from consanguineous parents with a complex phenotype including skeletal dysplasia associated with aortic stenosis, hypertrophic cardiomyopathy, hypodontia and amelogenesis imperfecta caused by a previously unreported homozygous LTBP3 splice site variant. We also compare the genotypes and phenotypes of patients reported to date. This work provides further evidence that brachyolmia with amelogenesis imperfecta is a distinct nosologic entity and that variations in LTBP3 are involved in its pathogenesis.


Asunto(s)
Amelogénesis Imperfecta/genética , Proteínas de Unión a TGF-beta Latente/genética , Osteocondrodisplasias/genética , Adolescente , Amelogénesis Imperfecta/complicaciones , Amelogénesis Imperfecta/diagnóstico , Consanguinidad , Humanos , Masculino , Osteocondrodisplasias/complicaciones , Osteocondrodisplasias/diagnóstico , Linaje , Perú , Fenotipo , Enfermedades Raras , Secuenciación del Exoma
14.
Am J Med Genet A ; 149A(4): 706-12, 2009 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-19248183

RESUMEN

A 36-year-old patient with a disorder characterized by severe mental retardation, behavioral problems, dysmorphic face, "muscular build," and hand/foot anomalies, is reported. Following a diagnosis of de novo pericentric inversion of chromosome 8 based on standard cytogenetic analysis, a subsequent 75 kb array-CGH investigation disclosed a deletion spanning for about 13.7 Mb in the 2q31.2q32.3 region. Whole painting of chromosome 8 established the intrachromosomal nature of the rearrangement and FISH analysis with locus-specific probes confirmed the deletion on the long arm of chromosome 2. The deleted region, clinical outcome, and medical history in this patient are mainly superimposable to those reported in a published 8-year-old boy, suggesting that this genomic segment is prone to rearrangements and its hemizygosity gives rise to a clinically recognizable syndrome. The role of some genes mapping in the deleted region and related with distinct disorders is discussed. Interestingly, deletion of MSTN gene, a negative regulator of muscle growth, was associated in our patient with a "muscular build," a feature which could be regarded as a handle for clinical recognition of this syndrome.


Asunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Cromosomas Humanos Par 2/genética , Discapacidad Intelectual/genética , Adulto , Inversión Cromosómica , Cromosomas Humanos Par 8/genética , Hibridación Genómica Comparativa , Anomalías Craneofaciales/genética , Deformidades Congénitas del Pie/genética , Deformidades Congénitas de la Mano/genética , Humanos , Hibridación Fluorescente in Situ , Masculino , Miostatina/genética , Fenotipo , Síndrome
15.
Eur J Hum Genet ; 27(8): 1260-1266, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30936464

RESUMEN

Schilbach-Rott syndrome (SRS, OMIM%164220) is a disorder of unknown aetiology that is characterised by hypotelorism, epichantal folds, cleft palate, dysmorphic face, hypospadia in males and mild mental retardation in some patients. To date, 5 families and 17 patients have exhibited this phenotype, and recurrence in two of these families suggests an autosomal dominant inheritance. SRS overlaps with a mild form of holoprosencephaly (HPE), but array-CGH analysis and sequencing of some HPE-related genes (SEPT9, SHH and TWIST) did not reveal any variants in at least one family. Herein, we investigated by array-CGH analysis a 11-year-old female patient and her father, both exhibiting the typical SRS phenotype, disclosing in the daughter-father couple the same microduplication of chromosome 9q22.32q22.33 [arr[hg19]9q22.32(98,049,611_98,049,636)x3,9q22.33 (99,301,483_99,301,508)x3], involving eight genes, including PTCH1. The duplication segregated with the disease, since it was not found in the healthy paternal grandparents of the proband. The gain-of-function variants of the PTCH1 gene are responsible for a mild form of HPE. This is the first genetic variant found in SRS. This finding reinforces the hypothesis that SRS belongs to the HPE clinical spectrum and suggests to perform array-CGH in patients with SRS phenotype and, if negative, to consider a potential benefit from sequencing of HPE-related genes.


Asunto(s)
Duplicación Cromosómica , Cromosomas Humanos Par 9/genética , Fisura del Paladar/genética , Anomalías Craneofaciales/genética , Duplicación de Gen , Holoprosencefalia/genética , Hipospadias/genética , Receptor Patched-1/genética , Niño , Fisura del Paladar/diagnóstico , Hibridación Genómica Comparativa , Anomalías Craneofaciales/diagnóstico , Padre , Femenino , Holoprosencefalia/diagnóstico , Humanos , Hipospadias/diagnóstico , Discapacidad Intelectual/genética , Masculino , Fenotipo
16.
J Clin Endocrinol Metab ; 102(11): 3961-3969, 2017 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-28938448

RESUMEN

Context: Familial isolated hypoparathyroidism (FIH) is a genetically heterogeneous disorder due to mutations of the calcium-sensing receptor (CASR), glial cells missing-2 (GCM2), guanine nucleotide binding protein α11 (GNA11), or parathyroid hormone (PTH) genes. Thus far, only four cases with homozygous and two cases with heterozygous mutations in the PTH gene have been reported. Objective: To clinically describe an FIH family and identify and characterize the causal gene mutation. Design: Genomic DNA of the family members was subjected to CASR, GCM2, GNA11, and PTH gene mutational analysis. Functional assays were performed on the variant identified. Participants: Six subjects of a three-generation FIH family with three affected individuals having severe hypocalcemia and inappropriately low serum PTH. Results: No mutations were detected in the CASR, GCM2, and GNA11 genes. A heterozygous variant that segregated with the disease was identified in PTH gene exon 2 (c.41T>A; p.M14K). This missense variant, in the hydrophobic core of the signal sequence, was predicted in silico to impair cleavage of preproPTH to proPTH. Functional assays in HEK293 cells demonstrated much greater retention intracellularly but impaired secretion into the medium of the M14K mutant relative to wild type. The addition of the pharmacological chaperone, 4-phenylbutyric acid, led to a reduction of cellular retention and increased accumulation in the cell medium of the M14K mutant. Conclusions: We report a heterozygous PTH mutation in an FIH family and demonstrate accumulation of the mutant intracellularly and its impaired secretion. An accurate genetic diagnosis in such hypoparathyroid patients is critical for appropriate treatment and genetic counseling.


Asunto(s)
Genes Dominantes , Hipoparatiroidismo/genética , Hormona Paratiroidea/genética , Señales de Clasificación de Proteína/genética , Adolescente , Adulto , Preescolar , Análisis Mutacional de ADN , Familia , Femenino , Células HEK293 , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Mutación , Hormona Paratiroidea/metabolismo , Linaje
18.
Science ; 295(5562): 2097-100, 2002 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-11896281

RESUMEN

T cells that accompany allogeneic hematopoietic grafts for treating leukemia enhance engraftment and mediate the graft-versus-leukemia effect. Unfortunately, alloreactive T cells also cause graft-versus-host disease (GVHD). T cell depletion prevents GVHD but increases the risk of graft rejection and leukemic relapse. In human transplants, we show that donor-versus-recipient natural killer (NK)-cell alloreactivity could eliminate leukemia relapse and graft rejection and protect patients against GVHD. In mice, the pretransplant infusion of alloreactive NK cells obviated the need for high-intensity conditioning and reduced GVHD. NK cell alloreactivity may thus provide a powerful tool for enhancing the efficacy and safety of allogeneic hematopoietic transplantation.


Asunto(s)
Trasplante de Médula Ósea/inmunología , Trasplante de Células Madre Hematopoyéticas , Células Asesinas Naturales/inmunología , Leucemia Mieloide/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Enfermedad Aguda , Animales , Células Presentadoras de Antígenos/inmunología , Supervivencia sin Enfermedad , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Efecto Injerto vs Leucemia , Antígenos H-2/inmunología , Haplotipos , Prueba de Histocompatibilidad , Humanos , Células Asesinas Naturales/trasplante , Leucemia Mieloide/inmunología , Ratones , Ratones Endogámicos NOD , Ratones Endogámicos , Ratones SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Receptores Inmunológicos/metabolismo , Receptores KIR , Recurrencia , Linfocitos T/inmunología , Acondicionamiento Pretrasplante
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