RESUMEN

Neu-Laxova syndrome (NLS) is a lethal genetic multiple congenital anomaly syndrome of unknown prevalence representing the severe spectrum of serine biosynthesis defects associated with PHGDH, PSAT1, or PSP gene mutations. The purpose of this study was to describe clinical/molecular and pathologic features of a NLS case caused by novel heterozygous missense variant in PHGDH gene identified in his consanguineous parents.

Asunto(s)

Anomalías Múltiples/genética , Encefalopatías/genética , Anomalías Congénitas/genética , Retardo del Crecimiento Fetal/genética , Ictiosis/genética , Deformidades Congénitas de las Extremidades/genética , Microcefalia/genética , Fosfoglicerato-Deshidrogenasa/genética , Mortinato/genética , Anomalías Múltiples/mortalidad , Anomalías Múltiples/patología , Encefalopatías/mortalidad , Encefalopatías/patología , Brasil/epidemiología , Anomalías Congénitas/mortalidad , Anomalías Congénitas/patología , Consanguinidad , Femenino , Retardo del Crecimiento Fetal/mortalidad , Retardo del Crecimiento Fetal/patología , Genes Letales/genética , Predisposición Genética a la Enfermedad , Humanos , Ictiosis/mortalidad , Ictiosis/patología , Deformidades Congénitas de las Extremidades/mortalidad , Deformidades Congénitas de las Extremidades/patología , Microcefalia/mortalidad , Microcefalia/patología , Mutación Missense/genética , Embarazo , Mortinato/epidemiología

RESUMEN

BACKGROUND: Oculo-auriculo-vertebral spectrum (OAVS) is a craniofacial developmental disorder that affects structures derived from the first and second pharyngeal arches. The clinically heterogeneous phenotype involves mandibular, oral, and ear development anomalies. Etiology is complex and poorly understood. Genetic factors have been associated, evidenced by chromosomal abnormalities affecting different genomic regions and genes. However, known pathogenic single-nucleotide variants (SNVs) have only been identified in MYT1 in a restricted number of patients. Therefore, investigations of SNVs on candidate genes may reveal other pathogenic mechanisms. METHODS: In a cohort of 73 patients, coding and untranslated regions (UTR) of 10 candidate genes (CRKL, YPEL1, MAPK1, NKX3-2, HMX1, MYT1, OTX2, GSC, PUF60, HOXA2) were sequenced. Rare SNVs were selected and in silico predictions were performed to ascertain pathogenicity. Likely pathogenic variants were validated by Sanger sequencing and heritability was assessed when possible. RESULTS: Four likely pathogenic variants in heterozygous state were identified in different patients. Two SNVs were located in the 5'UTR of YPEL1; one in the 3'UTR of CRKL and one in the 3'UTR of OTX2. CONCLUSION: Our work described variants in candidate genes for OAVS and supported the genetic heterogeneity of the spectrum.

Asunto(s)

Discapacidades del Desarrollo/patología , Polimorfismo de Nucleótido Simple , Proteínas Adaptadoras Transductoras de Señales/genética , Adolescente , Niño , Preescolar , Discapacidades del Desarrollo/genética , Femenino , Humanos , Lactante , Masculino , Proteínas Nucleares/genética , Factores de Transcripción Otx/genética , Regiones no Traducidas

RESUMEN

Patients with deletion of chromosome 13 present with variable clinical features, and the correlation between phenotype and genomic aberration is not well established in the literature, mainly due to variable sizes of the deleted segments and inaccuracy of breakpoint mapping. In order to improve the genotype-phenotype correlation, we obtained clinical and cytogenomic data from 5 Brazilian patients with different chromosome 13 deletions characterized by G-banding and array techniques. Breakpoints were nonrecurrent, with deletion sizes ranging from 3.8 to 43.3 Mb. Our patients showed some classic features associated with 13q deletion, independent of the location and size of the deletion: hypotonia, growth delay, psychomotor developmental delay, microcephaly, central nervous system anomalies, and minor facial dysmorphism as well as urogenital and limb abnormalities. Comparisons between the literature and our patients' data allowed us to narrow the critical regions that were previously reported for microphthalmia and urogenital abnormalities, indicating that gene haploinsufficiency of ARHGEF7, PCDH9 and DIAPH3, of MIR17HG and GPC6, and of EFNB2 may contribute to microcephaly, cardiovascular disease, and urogenital abnormalities, respectively. The knowledge about genes involved in the phenotypic features found in 13q deletion patients may help us to understand how the genes interact and contribute to their clinical phenotype, improving the patient's clinical follow-up.