RESUMO
Postaxial polydactyly (PAP) is a frequent limb malformation consisting in the duplication of the fifth digit of the hand or foot. Morphologically, this condition is divided into type A and B, with PAP-B corresponding to a more rudimentary extra-digit. Recently, biallelic truncating variants in the transcription factor GLI1 were reported to be associated with a recessive disorder, which in addition to PAP-A, may include syndromic features. Moreover, two heterozygous subjects carrying only one inactive copy of GLI1 were also identified with PAP. Herein, we aimed to determine the level of involvement of GLI1 in isolated PAP, a condition previously established to be autosomal dominantly inherited with incomplete penetrance. We analyzed the coding region of GLI1 in 95 independent probands with nonsyndromic PAP and found 11.57% of these subjects with single heterozygous pathogenic variants in this gene. The detected variants lead to premature termination codons or result in amino acid changes in the DNA-binding domain of GLI1 that diminish its transactivation activity. Family segregation analysis of these variants was consistent with dominant inheritance with incomplete penetrance. We conclude that heterozygous changes in GLI1 underlie a significant proportion of sporadic or familial cases of isolated PAP-A/B.
Assuntos
Dedos/anormalidades , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Heterozigoto , Polidactilia/diagnóstico , Polidactilia/genética , Dedos do Pé/anormalidades , Proteína GLI1 em Dedos de Zinco/genética , Alelos , Substituição de Aminoácidos , Feminino , Fibroblastos , Expressão Gênica , Genes Dominantes , Genes Reporter , Estudos de Associação Genética/métodos , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNAAssuntos
Talassemia/genética , Globinas delta/genética , Globinas épsilon/genética , gama-Globinas/genética , Transfusão de Sangue , Feminino , Sangue Fetal/química , Heterozigoto , Humanos , Recém-Nascido , Reação em Cadeia da Polimerase Multiplex , Talassemia/diagnóstico , Talassemia/embriologia , Talassemia/terapiaRESUMO
BACKGROUND: Only 15 point mutations in NFIX gene have been reported so far, nine of them cause the Marshall-Smith syndrome (MSS) and the remaining mutations lead to an overgrowth disorder with a less severe phenotype, defined as Sotos-like. METHODS: The clinical findings in three patients with MSS and two patients with a Sotos-like phenotype are presented. Analysis of the NFIX gene was performed both by conventional or next-generation sequencing. RESULTS: Five de novo mutations in NFIX gene were identified, four of them not previously reported. Two frameshift mutations and a donor-splice one caused MSS, while two missense mutations in the DNA binding/dimerisation domain entailed an overgrowth syndrome with some clinical features resembling Sotos syndrome, accompanied by a marfanoid habitus, very low BMI, long narrow face, or arachnodactyly. CONCLUSION: Marshall-Smith mutations are scattered through exons 6-10 of NFIX gene, while most point mutations causing an overgrowth syndrome are clustered in exon 2. Clinical features of this overgrowth syndrome may well be considered an intermediate phenotype between Sotos and Marfan syndromes.
Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Mutação , Fatores de Transcrição NFI/genética , Displasia Septo-Óptica/genética , Síndrome de Sotos/genética , Anormalidades Múltiplas/diagnóstico , Sequência de Aminoácidos , Sequência de Bases , Doenças do Desenvolvimento Ósseo/diagnóstico , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Análise Mutacional de DNA/métodos , Éxons , Evolução Fatal , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Fenótipo , Displasia Septo-Óptica/diagnóstico , Síndrome de Sotos/diagnóstico , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: The study of congenital defects (CD) must include termination of pregnancy (TOP) for CD and evaluate risk factors that modify their frequency. PATIENTS AND METHODS: Consecutive series of 517 newborn and 202 TOP with CD among 38,191 childbirths, between 1982-2009 years. RESULTS: The mean frequency for newborns with CD is 13.54 and for newborn and TOP with CD is 18.73. Single CD are 61.12% in newborns and 52.17% in TOP. The 18.37% of CD in newborn and 40.58% of TOP are syndromic. Mean gestational age for TOP is 17.92 weeks. Overall frequency of anencephaly is 2.62 for newborns and 6.77 for 10,000 for newborns and TOP. Spina bifida is 3.14 for 10,000 newborns and 5.99 for 10,000 newborns and TOP. Overall frequency of Down syndrome (DS) is 10.74 for 10,000 newborns and 22.14 for 10,000 newborns and TOP. The percentage of foreign mothers was 35.9% in 2009 and the mean maternal age significantly increased in this period. CONCLUSION: We observe a significant decrease of CD in newborns but not in their conception. We have not detected primary prevention for neural tube defects. The decrease in DS in newborns is not statistically relevant but ethnic diversity and maternal aging may be modifying the frequency. The 53% of CD were TOP in the period 2007-2009. It is mandatory a complete study for CD in TOP in order to offer serious reproductive counselling.