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1.
Genet Med ; 21(12): 2755-2764, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31263215

RESUMO

PURPOSE: Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A variants. METHODS: A large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a's role in renal development. RESULTS: Phenotypic details and variants of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic variant in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom presented with CAKUT/GD. Studies in Xenopus embryos demonstrated that knockdown of Dyrk1a, which is expressed in forming nephrons, disrupts the development of segments of embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by coinjecting wild-type human DYRK1A RNA, but not with DYRK1AR205* or DYRK1AL245R RNA. CONCLUSION: Evidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss-of-function studies in Xenopus substantiate a novel role for DYRK1A in GU development.

2.
J Genet Couns ; 28(4): 802-811, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30946507

RESUMO

The purpose of this study was to describe current genetic counseling practice in the United States following a non-invasive prenatal testing (NIPT) result positive for a sex chromosome abnormality (SCA). Screening for SCAs can be confounded by confined placental mosaicism, natural loss of the X chromosome from maternal cells during aging, and undiagnosed maternal SCA or copy number variant (CNV). Furthermore, with the exception of 45,X, individuals with SCAs usually have no ultrasound or postnatal findings. This makes follow-up for unresolved positive NIPT necessary; however, there are currently no clinical guidelines. This study used a cross-sectional design with an anonymous questionnaire to survey 176 genetic counselors. The majority of prenatal respondents always offered diagnostic testing (>88%) and anatomy ultrasound (~90%), but the percent consistently offering maternal karyotype (22%-52%) and postnatal evaluation (28%-87%) varied. Maternal karyotype was offered more often when NIPT was positive for 45,X or 47,XXX and patients had normal prenatal diagnostic testing (p < 0.02) or declined testing (p < 0.02). Offer of postnatal evaluation was more likely when diagnostic testing was declined (p < 0.001). The majority of pediatric providers always offered a postnatal karyotype for the newborn (>72%) but the percent offering maternal karyotype (6%-46%) varied widely. With the current inconsistencies, many newborns with undiagnosed SCAs who could benefit from growth hormone therapy, early intervention, and/or targeted surveillance may be missed. Therefore, there is a need for professional guidelines to help improve the consistency of clinical care for patients with NIPT results positive for SCAs.

3.
Prenat Diagn ; 39(5): 351-360, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30734934

RESUMO

OBJECTIVE: We evaluated what prenatal genetic counselor's (GCs) practices, attitudes, and barriers are in regards to prenatal microarray since the publication of the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) guidelines for microarray use. METHODS: This was a survey-based cross-sectional study of English-speaking, board certified or eligible GCs who currently practice prenatal genetic counseling. RESULTS: Of 192 respondents, 183 (95%) have incorporated chromosome microarray (CMA) into clinical practice, with 64% believing that the benefits of CMA outweigh the harms and 52% agreeing that CMA should be offered to all women regardless of indication. Those who reported being experts/comfortable in their knowledge of CMA (85%) and familiar with current clinical guidelines (86%) were significantly more likely to offer CMA to patients undergoing invasive testing and patients with fetal anomalies. Patient-specific concerns were the largest reported barrier (51%) when GCs do not offer CMA to patients. CONCLUSION: Our study demonstrates GCs follow guidelines for CMA use when specific indications are involved, but further guidelines are needed regarding CMA use for other routine indications where utility of CMA is not clearly understood. On this basis, ACOG and SMFM should continue revising their guidelines as more information comes to light regarding utility of prenatal CMA for all indications, and organizations like the National Society of Genetic Counselors (NSGC) should consider publishing guidelines on prenatal CMA that are specialized to the GCs sphere of practice.

4.
Am J Hum Genet ; 102(3): 487-493, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29478779

RESUMO

Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks that canalize development down one pathway while actively repressing the other. However, in contrast to testis formation, the gene regulatory pathways governing mammalian ovary development have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization or with testicular/ovotesticular disorders/differences of sex development (TDSD/OTDSD). We identified heterozygous frameshift mutations in NR2F2, encoding COUP-TF2, in three children. One carried a c.103_109delGGCGCCC (p.Gly35Argfs∗75) mutation, while two others carried a c.97_103delCCGCCCG (p.Pro33Alafs∗77) mutation. In two of three children the mutation was de novo. All three children presented with congenital heart disease (CHD), one child with congenital diaphragmatic hernia (CDH), and two children with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). The three children had androgen production, virilization of external genitalia, and biochemical or histological evidence of testicular tissue. We demonstrate a highly significant association between the NR2F2 loss-of-function mutations and this syndromic form of DSD (p = 2.44 × 10-8). We show that COUP-TF2 is highly abundant in a FOXL2-negative stromal cell population of the fetal human ovary. In contrast to the mouse, these data establish COUP-TF2 as a human "pro-ovary" and "anti-testis" sex-determining factor in female gonads. Furthermore, the data presented here provide additional evidence of the emerging importance of nuclear receptors in establishing human ovarian identity and indicate that nuclear receptors may have divergent functions in mouse and human biology.

5.
Adv Chronic Kidney Dis ; 24(6): 372-379, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29229168

RESUMO

Hypertension (HT) is a public health problem in children particularly related to the epidemic of overweight and obesity. Monogenic forms of HT are important in the differential diagnosis in children presenting with severe or refractory HT, who have a family history of early-onset HT, unusual physical examination findings, and/or characteristic hormonal and biochemical abnormalities. Most genetic defects in these disorders ultimately result in increased sodium transport in the distal nephron resulting in volume expansion and HT. Genetic testing, which is increasingly available, has diagnostic, therapeutic, and predictive implications for families affected by these rare conditions.


Assuntos
Hipertensão , Idade de Início , Transporte Biológico Ativo/fisiologia , Criança , Diagnóstico Diferencial , Testes Genéticos , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/genética , Néfrons/metabolismo
6.
Am J Hum Genet ; 100(6): 907-925, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575647

RESUMO

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.


Assuntos
Cromatina/metabolismo , Haploinsuficiência/genética , Deficiência Intelectual/genética , Transcrição Genética , Fator de Transcrição YY1/genética , Acetilação , Adolescente , Sequência de Bases , Pré-Escolar , Imunoprecipitação da Cromatina , Estudos de Coortes , Elementos Facilitadores Genéticos/genética , Feminino , Ontologia Genética , Haplótipos/genética , Hemizigoto , Histonas/metabolismo , Humanos , Linfócitos/metabolismo , Masculino , Metilação , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Ligação Proteica/genética , Domínios Proteicos , Fator de Transcrição YY1/química
7.
Eur J Med Genet ; 60(7): 391-394, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28442439

RESUMO

Marshall-Smith Syndrome (MRSHSS) is a very rare genetic disorder characterized by failure to thrive and characteristic dysmorphic features associated with accelerated osseous maturation. We present a nine-year-old girl who was diagnosed with MRSHSS based on characteristic clinical features supported by the identification of a novel de novo pathogenic variant in the NFIX gene. The patient also presented with precocious puberty diagnosed at five years of age and had an abnormal GnRH stimulation test indicative of central precocious puberty. Central precocious puberty has not been described in association with MRSHSS previously in the medical literature and broadens our knowledge of the natural history of MRSHSS. The causes of advanced bone age in this syndrome are also reviewed. Additionally, the patient showed progressive dilatation of the aortic root. Although connective tissue abnormalities have been described in association with MRSHSS, aortic root dilatation has not. Understanding the mechanism of comorbidities such as advanced bone age and aortic root dilatation in MRSHSS patients enables future development of anticipatory guidance, preventative care measures, and treatment guidelines.


Assuntos
Anormalidades Múltiplas/genética , Doenças da Aorta/genética , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Mutação , Fatores de Transcrição NFI/genética , Puberdade Precoce/genética , Displasia Septo-Óptica/genética , Anormalidades Múltiplas/diagnóstico , Adulto , Doenças da Aorta/diagnóstico , Doenças do Desenvolvimento Ósseo/diagnóstico , Criança , Anormalidades Craniofaciais/diagnóstico , Feminino , Humanos , Masculino , Puberdade Precoce/diagnóstico , Displasia Septo-Óptica/diagnóstico
8.
Eur J Med Genet ; 60(6): 285-288, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28359930

RESUMO

Wiedemann-Steiner syndrome (WDSTS) is a very rare genetic disorder characterized by short stature, intellectual disability and distinctive facial appearance. We present a five-year-old boy who was diagnosed with WDSTS based on identification of a novel de novo pathogenic variant in the KMT2A gene (OMIM: 159555) by Whole Exome Sequencing and supported by some characteristic clinical features. Genotype and phenotype of the patient is compared with the earlier reported patients in the literature, in an attempt to broaden our knowledge of this rare syndrome.


Assuntos
Anormalidades Múltiplas/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Mutação , Proteína de Leucina Linfoide-Mieloide/genética , Anormalidades Múltiplas/diagnóstico , Criança , Exoma , Genótipo , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Fenótipo , Síndrome
9.
J Pediatr Endocrinol Metab ; 29(9): 1089-93, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27487489

RESUMO

Permanent neonatal diabetes (PNDM) is a rare genetic condition characterized by hyperglycemia, insulinopenia, and failure to thrive beginning in the first 6 months of life. Recessive mutations in INS lead to decreased production of insulin via a variety of mechanisms. We present a case of two brothers, born to consanguineous parents, with a novel homozygous intronic variant in the INS gene. Each patient presented with intrauterine growth restriction (IUGR) and significant hyperglycemia within the first 24 h of life. All the grandparents have a diagnosis of diabetes, one of them requiring insulin treatment and the parents currently deny personal histories of diabetes. Although this mutation has not previously been described, given the segregation of the mutation, absence of heterozygosity (AOH) in the genomic region encompassing the INS locus, documented insulinopenia, and high neonatal insulin requirements, we suspect that this variant is pathogenic. Possible implications for personalized treatment of the underlying molecular etiology for an individual's diabetes are discussed.


Assuntos
Diabetes Mellitus/etiologia , Insulina/genética , Íntrons/genética , Mutação/genética , Adulto , Consanguinidade , Feminino , Homozigoto , Humanos , Recém-Nascido , Masculino , Linhagem , Prognóstico , Irmãos
10.
Curr Opin Pediatr ; 27(6): 675-84, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26335769

RESUMO

PURPOSE OF REVIEW: Disorders of sexual development (DSD) are a genetic and phenotypic heterogeneous group of congenital disorders. This review focuses on the genetics of DSD and aims to recognize and contextualize, in a systematic way, based on the classification and the genetic mechanisms, the latest developments in the field of DSD diagnostics. RECENT FINDINGS: Due to the current diagnostic armamentarium, during the past decade, the field of DSD diagnostics has changed dramatically from the recognition of few genes and cytogenetic abnormalities, to the identification of multiple genes and a wide arrange of genetic mechanisms involved in the genesis of DSD. In addition, the phenotypes associated with the genetic mechanism have expanded tremendously. SUMMARY: Despite the current diagnostic limitations, the landscape for genetics of DSD is encouraging due to discovery of new genes, their interactions, and the recognition of the variety of mechanisms involved.


Assuntos
Cromossomos Humanos X/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Disgenesia Gonadal 46 XX/genética , Mutação/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Exame Físico/métodos , Quimerismo , Disgenesia Gonadal 46 XX/diagnóstico , Disgenesia Gonadal 46 XX/fisiopatologia , Hormônios Esteroides Gonadais/sangue , Humanos , Cariótipo , Anamnese , Mosaicismo , Fenótipo
11.
J Clin Endocrinol Metab ; 100(10): E1353-61, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26204134

RESUMO

CONTEXT: Iodide (I(-)), an essential constituent of the thyroid hormones, is actively accumulated in the thyroid by the Na(+)/I(-) symporter (NIS), a key plasma membrane protein encoded by the slc5a5 gene. Mutations in slc5a5 cause I(-) transport defects (ITDs), autosomal-recessive disorders in which I(-) accumulation is totally or partially impaired, leading to congenital hypothyroidism. The characterization of NIS mutants has yielded significant insights into the molecular mechanism of NIS. OBJECTIVE: This study aimed to determine the basis of a patient's ITD clinical phenotype, by sequencing her slc5a5 gene. DESIGN: Genomic DNA was purified and the slc5a5 gene sequence determined. Functional in vitro studies were performed to characterize the V270E NIS mutant. PATIENT: The index patient was diagnosed with hypothyroidism with minimal radioiodide uptake in a normally located, although enlarged, thyroid gland. RESULTS: We identified a new NIS mutation: V270E. The patient had the compound heterozygous NIS mutation R124H/V270E. R124H NIS has been characterized previously. We show that V270E markedly reduces I(-) uptake via a pronounced (but not total) impairment of the protein's plasma membrane targeting. Remarkably, V270E is intrinsically active. Therefore, a negative charge at position 270 interferes with NIS cell surface trafficking. The patient's minimal I(-) uptake enabled sufficient thyroid hormone biosynthesis to prevent cognitive impairment. CONCLUSIONS: A nonpolar residue at position 270, which all members of the SLC5A family have, is required for NIS plasma membrane targeting.


Assuntos
Transtornos Cognitivos/genética , Transtornos do Crescimento/genética , Mutação , Simportadores/genética , Alelos , Criança , Hipotireoidismo Congênito/genética , Análise Mutacional de DNA , Feminino , Humanos , Fenótipo
12.
Am J Med Genet A ; 167A(4): 872-7, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25708669

RESUMO

We report on a pair of normally conceived monochorionic/dizygotic (MC/DZ) sex discordant twins. The comparison of blood and skin genotypes revealed that the chimerism was also present in the skin. We conjecture about the developmental origins of this case.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Anormalidades Múltiplas/diagnóstico , Gêmeos Dizigóticos/genética , Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Múltiplas/genética , Quimerismo , Feminino , Humanos , Lactente , Masculino , Polimorfismo de Nucleotídeo Único , Pele/patologia
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