The oculoauriculovertebral spectrum (OAVS) is characterized by anomalies involving the development of the first and second pharyngeal arches during the embryonic period. The phenotype is highly heterogeneous, involving ears, eyes, face, neck, and other systems and organs. There is no agreement in the literature for the minimum phenotypic inclusion criteria, but the primary phenotype involves hemifacial microsomia with facial asymmetry and microtia. Most cases are sporadic and the etiology of this syndrome is not well known. Environmental factors, family cases that demonstrate Mendelian inheritance, such as preauricular appendages, microtia, mandibular hypoplasia, and facial asymmetry; chromosomal abnormalities and some candidate genes suggest a multifactorial inheritance model. We evaluated clinical, cytogenomic and molecularly 72 patients with OAVS, and compared our findings with patients from the literature. We found 15 CNVs (copy number variations) considered pathogenic or possibly pathogenic in 13 out of 72 patients. Our results did not indicated a single candidate genomic region, but recurrent chromosomal imbalances were observed in chromosome 4 and 22, in regions containing genes relevant to the OAVS phenotype or related to known OMIM diseases suggesting different pathogenic mechanisms involved in this genetically and phenotypic heterogeneous spectrum.

Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder characterized by hemifacial microsomia associated with ear, eyes and vertebrae malformations showing highly variable expressivity. Recently, MYT1, encoding the myelin transcription factor 1, was reported as the first gene involved in OAVS, within the retinoic acid (RA) pathway. Fifty-seven OAVS patients originating from Brazil were screened for MYT1 variants. A novel de novo missense variant affecting function, c.323C>T (p.(Ser108Leu)), was identified in MYT1, in a patient presenting with a severe form of OAVS. Functional studies showed that MYT1 overexpression downregulated all RA receptors genes (RARA, RARB, RARG), involved in RA-mediated transcription, whereas no effect was observed on CYP26A1 expression, the major enzyme involved in RA degradation, Moreover, MYT1 variants impacted significantly the expression of these genes, further supporting their pathogenicity. In conclusion, a third variant affecting function in MYT1 was identified as a cause of OAVS. Furthermore, we confirmed MYT1 connection to RA signaling pathway.

Detailed molecular characterization of chromosomal rearrangements involving X-chromosome has been a key strategy in identifying X-linked intellectual disability-causing genes. We fine-mapped the breakpoints in four women with balanced X-autosome translocations and variable phenotypes, in order to investigate the corresponding genetic contribution to intellectual disability. We addressed the impact of the gene interruptions in transcription and discussed the consequences of their functional impairment in neurodevelopment. Three patients presented with cognitive impairment, reinforcing the association between the disrupted genes (TSPAN7-MRX58, KIAA2022-MRX98, and IL1RAPL1-MRX21/34) and intellectual disability. While gene expression analysis showed absence of TSPAN7 and KIAA2022 expression in the patients, the unexpected expression of IL1RAPL1 suggested a fusion transcript ZNF611-IL1RAPL1 under the control of the ZNF611 promoter, gene disrupted at the autosomal breakpoint. The X-chromosomal breakpoint definition in the fourth patient, a woman with normal intellectual abilities, revealed disruption of the ZDHHC15 gene (MRX91). The expression assays did not detect ZDHHC15 gene expression in the patient, thus questioning its involvement in intellectual disability. Revealing the disruption of an X-linked intellectual disability-related gene in patients with balanced X-autosome translocation is a useful tool for a better characterization of critical genes in neurodevelopment. © 2015 Wiley Periodicals, Inc.

BackgroundOculo‐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. MethodsIn 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.ResultsFour 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.ConclusionOur work described variants in candidate genes for OAVS and supported the genetic heterogeneity of the spectrum.

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.