Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 51
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Am J Med Genet A ; 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33438813

RESUMO

At the 43rd annual meeting of the ASHG in 1993, the senior author reported monozygotic twins with discordant phenotype due to a ring 13 chromosomal mosaic syndrome in one of them. Her major manifestations included: intrauterine growth restriction (IUGR), failure to thrive (FTT), delayed developmental milestones/intellectual disability (DDM/ID), left hemihypoplasia of her body with leg length discrepancy, left profound deafness due to inner ear malformation, telecanthus, dental anomalies mainly on the left side, congenital torticollis due to Klippel-Feil anomaly, 13 ribs, scoliosis, dislocation of the left hip, and distinctive left hand and feet. A blood karyotype at age 31/2 was normal. Silver-Russell syndrome was initially suspected; however, at age 4, a karyotype on skin fibroblasts showed a ring 13 chromosomal mosaicism, 46,XX,15s+/46,XX,-13,+r(13),15s+, with a higher frequency on the left side of the body. Since then, we have been involved in the management of this patient for 30 years. This has ultimately allowed us to compare her achievements with her normal monozygotic twin. In this long term follow-up, we want to emphasize the importance of: (a) early recognition of genetic syndromes, especially of mosaicisms, and of early intervention programs, (b) the involvement of different specialists in the management of patients with MCA, and (c) mentioning how familial and socioeconomic issues may limit or enhance the full potential of patients with some genetic disorders.

2.
Am J Med Genet A ; 185(3): 916-922, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33369125

RESUMO

ALX4 is a homeobox gene expressed in the mesenchyme of developing bone and is known to play an important role in the regulation of osteogenesis. Enlarged parietal foramina (EPF) is a phenotype of delayed intramembranous ossification of calvarial bones due to variants of ALX4. The contrasting phenotype of premature ossification of sutures is observed with heterozygous loss-of-function variants of TWIST1, which is an important regulator of osteoblast differentiation. Here, we describe an individual with a large cranium defect, with dominant transmission from the mother, both carrying disease causing heterozygous variants in ALX4 and TWIST1. The distinct phenotype of absent superior and posterior calvarium in the child and his mother was in sharp contrast to the other affected maternal relatives with a recognizable ALX4-related EPF phenotype. This report demonstrates comorbid disorders of Saethre-Chotzen syndrome and EPF in a mother and her child, resulting in severe skull defects reminiscent of calvarial abnormalities observed with bilallelic ALX4 variants. To our knowledge this is the first instance of ALX4 and TWIST1 variants acting synergistically to cause a unique phenotype influencing skull ossification.

3.
Am J Med Genet A ; 182(7): 1785-1790, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32324310

RESUMO

Basel-Vanagaite-Smirin-Yosef syndrome is a recently described autosomal recessive intellectual disability syndrome caused by variants in the MED25 gene. While it was originally identified in Brazil, it was further described in Israel by authors who are now the namesake of the condition. A 2018 publication further contributed to its delineation, but the patient's phenotype was complicated by a dual diagnosis. More recently, an article describing a set of affected siblings was published. We describe three, previously unreported, patients showing clinical variability for this newly defined syndrome. The major features determined by "reverse phenotyping" include significant to profound developmental delays/intellectual disability with absent or delayed speech, epilepsy, ocular abnormalities, cleft lip and/or palate, congenital heart disease, urogenital anomalies, skeletal abnormalities, brain malformations and/or microcephaly, failure to thrive, and dysmorphic features. The authors suggest the delineation of an acronym using the gene name and common features seen across the majority of patients reported so far. This new nomination, MED-DOCS, may help clinicians to recognize, suspect, and remember this novel syndrome.

4.
Am J Med Genet A ; 182(7): 1767-1775, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32297715

RESUMO

Autosomal recessive SOPH syndrome was first described in the Yakuts population of Asia by Maksimova et al. in 2010. It arises from biallelic pathogenic variants in the NBAS gene and is characterized by severe postnatal growth retardation, senile facial appearance, small hands and feet, optic atrophy with loss of visual acuity and color vision, and normal intelligence (OMIM #614800). The presence of Pelger-Hüet anomaly in this disorder led to its name as an acronym for Short stature, Optic nerve atrophy, and Pelger-Hüet anomaly. Recent publications have further contributed to the characterization of this syndrome through additional phenotype-genotype correlations. We review the clinical features described in these publications and report on a 27-year-old woman with dwarfism with osteolysis and multiple skeletal problems, minor anomalies, immunodeficiency, diabetes mellitus, and multiple secondary medical problems. Her condition was considered an unknown autosomal recessive disorder for many years until exome sequencing provided the diagnosis by revealing a founder disease-causing variant that was compound heterozygous with a novel pathogenic variant in NBAS. Based on the major clinical features of this individual and others reported earlier, a revision of the acronym is warranted to facilitate clinical recognition.

5.
Eur J Med Genet ; 63(4): 103842, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31945512

RESUMO

Gorlin syndrome, also known as Nevoid Basal-Cell Carcinoma Syndrome (NBCCS), is an autosomal dominant tumor predisposition syndrome that presents early in life with characteristic congenital malformations and tumors. This syndrome most commonly results from germline mutations of the PTCH1 tumor suppressor gene, which shows high penetrance and great intra and interfamilial phenotypic variability, as well as the SUFU tumor suppressor gene. Recently, the PTCH2 gene has also been implicated as a cause of Gorlin syndrome. Notably, these patients displayed milder phenotypes of Gorlin syndrome when considered against PTCH1 and SUFU-related disease. We report a patient with a novel PTCH2 mutation inherited from his father. The proband displays several minor diagnostic features of Gorlin syndrome, supporting the pathogenic role of this gene. Features in the proband include macrocephaly, a wide face, prominent forehead, hypertelorism/telecanthus, large eyes, cleft lip and palate, thin vertical palmar creases, penoscrotal inversion, and a hyperpigmented spot on his penis. His father displays macrocephaly, several nevi on his back and shoulders, and a single palmar pit on his left hand, raising suspicion for Gorlin syndrome. Whole exome sequence (trio) found that the proband and father are heterozygous for NM_003738.4:c.3347C>T;p.(Pro1116Leu) in exon 21 of PTCH2, found also in his mildly affected brother. This semi-conservative amino acid substitution has been reported in the literature, but its significance is unclear. Notably, the proband, brother, and father do not meet clinical criteria for Gorlin syndrome. However, the clinical findings described in this family support the association between PTCH2 mutations and Gorlin-like phenotypes.

6.
Am J Med Genet A ; 179(7): 1276-1286, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31124279

RESUMO

Lysine-specific demethylase 6B (KDM6B) demethylates trimethylated lysine-27 on histone H3. The methylation and demethylation of histone proteins affects gene expression during development. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple neurodevelopmental disorders. We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings. Our findings will allow for further investigation in to the role of the KDM6B gene in human neurodevelopmental disorders.


Assuntos
Variação Genética , Histona Desmetilases com o Domínio Jumonji/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino
8.
Cleft Palate Craniofac J ; 56(5): 674-678, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30343593

RESUMO

We report 2 cases of mandibulofacial dysostosis with microcephaly (MFDM) with different and novel de novo mutations in the elongation factor Tu GTP binding domain containing 2 gene. Both cases were initially thought to have alternative disorders but were later correctly diagnosed through whole-exome sequencing. These cases expand upon our knowledge of the phenotypic spectrum in patients with MFDM, which will aid in defining the full phenotype of this disorder and increase awareness of this condition.


Assuntos
Disostose Mandibulofacial , Fatores de Alongamento de Peptídeos/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Humanos , Disostose Mandibulofacial/genética , Microcefalia , Mutação , Fenótipo
9.
PLoS Genet ; 14(11): e1007671, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30500825

RESUMO

Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p = 4.93 x 10(-11)) than expected from the estimated random mutation rate. Further, all de novo variants described here affect residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. The affected residues are highly conserved across both RAL- and RAS-family genes, are devoid of variation in large human population datasets, and several are homologous to positions at which disease-associated variants have been observed in other GTPase genes. We directly assayed GTP hydrolysis and RALA effector-protein binding of the observed variants, and found that all but one tested variant significantly reduced both activities compared to wild-type. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Proteínas Mitocondriais/genética , Mutação , Domínios e Motivos de Interação entre Proteínas/genética , Proteínas ral de Ligação ao GTP/genética , Proteínas ras/genética , Facies , Genótipo , Guanosina Difosfato/metabolismo , Guanosina Trifosfato/metabolismo , Humanos , Proteínas Mitocondriais/química , Modelos Moleculares , Mutação de Sentido Incorreto , Fenótipo , Conformação Proteica , Proteínas ral de Ligação ao GTP/química , Proteínas ras/química
10.
Am J Med Genet A ; 176(12): 2564-2574, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30302899

RESUMO

Schaaf-Yang Syndrome (SYS) is a genetic disorder caused by truncating pathogenic variants in the paternal allele of the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13. SYS is a neurodevelopmental disorder that has clinical overlap with Prader-Willi Syndrome in the initial stages of life but becomes increasingly distinct throughout childhood and adolescence. Here, we describe the phenotype of an international cohort of 78 patients with nonsense or frameshift mutations in MAGEL2. This cohort includes 43 individuals that have been reported previously, as well as 35 newly identified individuals with confirmed pathogenic genetic variants. We emphasize that intellectual disability/developmental delay, autism spectrum disorder, neonatal hypotonia, infantile feeding problems, and distal joint contractures are the most consistently shared features of patients with SYS. Our results also indicate that there is a marked prevalence of infantile respiratory distress, gastroesophageal reflux, chronic constipation, skeletal abnormalities, sleep apnea, and temperature instability. While there are many shared features, patients with SYS are characterized by a wide phenotypic spectrum, including a variable degree of intellectual disability, language development, and motor milestones. Our results indicate that the variation in phenotypic severity may depend on the specific location of the truncating mutation, suggestive of a genotype-phenotype association. This evidence may be useful in both prenatal and pediatric genetic counseling.


Assuntos
Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Proteínas/genética , Adolescente , Criança , Pré-Escolar , Códon sem Sentido , Feminino , Mutação da Fase de Leitura , Estudos de Associação Genética , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Fenótipo , Síndrome , Adulto Jovem
11.
Eur J Med Genet ; 61(1): 21-23, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29024830

RESUMO

Baraitser-Winter syndrome was first described as a syndrome of iris coloboma, ptosis, hypertelorism, and mental retardation (Baraitser and Winter 1988; Baraitser, 2016). The phenotypic spectrum has since broadened to include other facial dysmorphic features, deafness, microcephaly, lissencephaly, and CNS findings (Baraitser and Winter 1988; Ganesh et al., 2005; Henedy et al., 2010; Verloes et al., 2015). The syndrome is due to pathogenic variants on either ACTB or ACTG1 genes (Di Donato et al., 2014; Rivière et al., 2012). There is still discussion which gene variant produces a more severe phenotype (Di Donato et al., 2016; Di Donato et al., 2014; Verloes et al., 2015). We report a 3-year-old girl with short stature, mild global developmental delay, minor brain anomalies and few dysmorphic features including unusual stroma of the irises and unreported corectopia. Exome sequencing reported a de novo likely pathogenic variant on the ACTB gene. The present report adds a new ocular finding to the phenotypic spectrum.


Assuntos
Coloboma/patologia , Anormalidades Craniofaciais/patologia , Deficiência Intelectual/patologia , Iris/patologia , Actinas/genética , Pré-Escolar , Coloboma/genética , Anormalidades Craniofaciais/genética , Feminino , Humanos , Deficiência Intelectual/genética , Fenótipo , Síndrome
12.
Clin Dysmorphol ; 26(4): 195-199, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28777121

RESUMO

Noonan syndrome (NS) is an autosomal dominant disorder characterized by distinctive facial features, short neck, short stature, congenital heart defects, pectus deformities, and variable developmental delays. NS is genetically heterogeneous as pathogenic variants in several genes involved in the Ras/mitogen-activated protein kinase pathway have been associated with a NS phenotype. Overall, 50% of patients harbor pathogenic variants in PTPN11, whereas 3-17% of patients have variants in RAF1. We present two premature neonates with progressive biventricular hypertrophy found to have RAF1 variants in the CR2 domain. Molecular testing in patient 1 revealed a missense variant of a highly conserved residue c.782 C>G (p.P261R). This variant has been reported once with fatal outcome. Patient 2 also had a missense variant in a highly conserved neighboring residue c.770 C>T (p.S257L). This variant has been previously reported, most recently associated with the development of pulmonary arterial hypertension. Both our patients had prenatal findings of polyhydramnios, short long bones, hydrops fetalis, and cardiac anomalies with progressive biventricular hypertrophic cardiomyopathy. Both patients had a lethal outcome. Our findings further support the pathogenicity and lethality of p.P261R, and the need to monitor for pulmonary arterial hypertension in p.S257L. In addition, the second patient was presented with progressive hydrocephalus due to aqueductal stenosis. This could be related to the NS phenotype. More cases with this association are needed to confirm this finding.


Assuntos
Cardiomiopatia Hipertrófica/genética , Ventrículos do Coração/patologia , Mutação/genética , Proteínas Proto-Oncogênicas c-raf/genética , Evolução Fatal , Humanos , Recém-Nascido , Masculino , Fenótipo
13.
Clin Case Rep ; 5(4): 431-434, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28396763

RESUMO

We report on a newborn with IUGR, rhizomelic dwarfism, and suspected chondrodysplasia punctata. At birth, OI was suspected; however, a skeletal survey suggested ML II alpha/beta. Sequencing revealed compound heterozygosity for a reported pathogenic and novel but expected pathogenic GNPTAB variant. Molecular testing for autosomal recessive OI identified a SERPINF1 variant.

15.
Eur J Med Genet ; 59(4): 227-31, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26855056

RESUMO

Neonatal severe hyperparathyroidism (NSHPT) is a rare, life-threatening condition that presents with severe hypercalcemia, hyperparathyroidism, and osteopenia in the newborn period. Treatment of NSHPT traditionally includes hydration and bisphosphonates; however newer calcimimetic agents, such as cinacalcet, are now being utilized to prevent or delay parathyroidectomy which is technically difficult in the newborn. Medical treatment success is related to calcium sensing receptor (CaSR) genotype. We report a 4-day-old infant who presented with hyperbilirubinemia, poor feeding, weight loss, severe hypotonia and was ultimately diagnosed with NSHPT. The patient's total serum calcium level of 36.8 mg/dL (reference range: 8.5-10.4 mg/dL) is, to our knowledge, the highest ever documented in this setting. Exome data previously obtained on the infant's parents was re-analyzed demonstrating bi-parental heterozygosity for a mutation of the CASR gene: c.206G > A, and Sanger sequencing data confirmed the patient was a homozygote for the same mutation. Though a patient with the same CaSR gene mutation described here has responded to cinacalcet, our patient did not respond and required parathyroidectomy. Though this case has previously been published as a surgical case report, a full report of the medical management and underlying genetic etiology is warranted; this case underscores the importance of disclosing bi-parental heterozygosity for a gene causing severe neonatal disease particularly when treatment is available and illustrates the need for further in vitro studies of this CaSR mutation.


Assuntos
Hiperbilirrubinemia/genética , Hipercalcemia/genética , Hiperparatireoidismo/genética , Receptores de Detecção de Cálcio/genética , Genótipo , Humanos , Hiperbilirrubinemia/patologia , Hipercalcemia/fisiopatologia , Hiperparatireoidismo/fisiopatologia , Hiperparatireoidismo/cirurgia , Recém-Nascido , Mutação , Paratireoidectomia
16.
Rev. Méd. Clín. Condes ; 26(4): 452-457, jul. 2015. tab
Artigo em Espanhol | LILACS | ID: biblio-1129071

RESUMO

Dismorfología se refiere al estudio de los pacientes con malformaciones congénitas. En este concepto se incluyen también pacientes con otras alteraciones morfológicas que lo hacen aparecer diferente. En este artículo revisamos los diferentes tipos de alteraciones que el médico debe reconocer, tanto cualitativas, como malformaciones, deformaciones, disrupciones y displasias, como cuantitativas enfatizando la importancia de diferenciar si éstas constituyen variación normal, racial o familiar, o son indicadores de una afección genética. Delinearemos la forma de estudiar al paciente y los problemas más frecuentes que dificultan establecer el diagnóstico. Si la malformación es aislada, de causa poligénica/multifactorial, es habitualmente el médico tratante quien establece el diagnóstico y otorga asesoramiento genético. En caso de anomalías múltiples, en que hay que determinar su etiología específica, lo recomendable es referir el paciente a un genetista clínico. Sólo así se podrá dar asesoramiento genético responsable ayudando al paciente a lograr su máximo potencial genético y a la familia a tener hijos normales.


Dysmorphology refers to the study of patients with congenital malformations. However, dysmorphology not only includes the study of birth defects but also the study of patients with other anomalies making him/her look different. In this article we review qualitative abnormalities, such us malformations, deformations, disruptions and displasias as well as quantitative variations which may represent normal, racial or familial, variation or be part of a genetic disorder. We review the study of the patient and frequent diagnostic problems. If the congenital anomaly is isolated, non-syndromic, of polygenic/multifactorial etiology, it is the responsibility of the primary physician to establish the diagnosis and provide genetic counseling. However, in cases of multiple anomalies when the physician should establish the specific etiology, the recommendation is to refer the patient to a clinical geneticist. The main goal of the evaluation is to determine the etiology of the abnormalities. Only then can the physician provide responsible genetic counseling, helping the patient to achieve his/her maximum genetic potential and allow the family to have normal children.


Assuntos
Humanos , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/etiologia
18.
Hum Mutat ; 35(12): 1469-75, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25205021

RESUMO

Approximately 5% of all patients with neurofibromatosis type-1 (NF1) exhibit large deletions of the NF1 gene region. To date, only nine unrelated cases of large NF1 duplications have been reported, with none of the affected patients exhibiting multiple café au lait spots (CALS), Lisch nodules, freckling, or neurofibromas, the hallmark signs of NF1. Here, we have characterized two novel NF1 duplications, one sporadic and one familial. Both index patients with NF1 duplications exhibited learning disabilities and atypical CALS. Additionally, patient R609021 had Lisch nodules, whereas patient R653070 exhibited two inguinal freckles. The mother and sister of patient R609021 also harbored the NF1 duplication and exhibited cognitive dysfunction but no CALS. The breakpoints of the nine NF1 duplications reported previously have not been identified and hence their underlying generative mechanisms have remained unclear. In this study, we performed high-resolution breakpoint analysis that indicated that the two duplications studied were mediated by nonallelic homologous recombination (NAHR) and that the duplication breakpoints were located within the NAHR hotspot paralogous recombination site 2 (PRS2), which also harbors the type-1 NF1 deletion breakpoints. Hence, our study indicates for the first time that NF1 duplications are reciprocal to type-1 NF1 deletions and originate from the same NAHR events.


Assuntos
Deleção de Genes , Duplicação Gênica , Genes da Neurofibromatose 1 , Recombinação Homóloga , Adolescente , Criança , Humanos
19.
Eur J Med Genet ; 57(10): 562-6, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25118007

RESUMO

We report an African-American family that was identified after the proposita was referred for diagnostic evaluation at 4½ months with a history of Hirschsprung and dysmorphic features typical of Waardenburg syndrome (WS). Family evaluation revealed that the father had heterochromidia irides and hypertelorism supporting the clinical diagnosis of WS; however, examination of the mother revealed characteristic facial and digital features of Coffin-Lowry syndrome (CLS). Molecular testing of the mother identified a novel 2 bp deletion (c.865_866delCA) in codon 289 of RPS6KA3 leading to a frame-shift and premature termination of translation 5 codons downstream (NM_004586.2:p.Gln289ValfsX5). This deletion also was identified in the proposita and her three sisters with a clinical suspicion of CLS, all of whom as carriers for this X-linked disorder had very subtle manifestations. The molecular confirmation of WS type 4 (Shah-Waardenburg; WS4) was not as straightforward. To evaluate WS types 1-4, multiple sequential molecular tests were requested, including Sanger sequencing of all exons, and deletion/duplication analysis using MLPA for PAX3, MITF, SOX10, EDN3 and EDNRB. Although sequencing did not identify any disease causing variants, MLPA identified a heterozygous deletion of the entire EDNRB in the father. This deletion was also found in the proposita and the oldest child. Since the heterozygous deletion was the only change identified in EDNRB, this family represents one of the few cases of an autosomal dominant inheritance of WS4 involving the endothelin pathway. Altogether, clinical evaluation of the family revealed one child to be positive for WS4 and two positive for CLS, while two children were positive for both diseases simultaneously (including the proposita) while another pair test negative for either disease. This kinship is an example of the coincidence of two conditions co-segregating in one family, with variable phenotypes requiring molecular testing to confirm the clinical diagnoses.


Assuntos
Deleção Cromossômica , Síndrome de Coffin-Lowry/genética , Receptores de Endotelina/genética , Síndrome de Waardenburg/genética , Adulto , Afro-Americanos , Sequência de Bases , Criança , Segregação de Cromossomos , Cromossomos Humanos X , Códon , Comorbidade , DNA , Análise Mutacional de DNA , Éxons , Feminino , Genes Dominantes , Hereditariedade , Doença de Hirschsprung , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Núcleo Familiar , Linhagem , Receptor de Endotelina B
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA