Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia

International audienceAnophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non-syndromic forms of AM. We screened seven AM genes [GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y-box 2), and VSX2 (visual system homeobox 2 gene)] in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX) were identified using a semi-quantitative multiplex polymerase chain reaction (PCR) [quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF)]. The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling

Identification of two homozygous mutations, in the male reproductive tract specific beta-defensin 126/128 genes, potentially underlie a severe sperm dysfunction

Introduction: Hereditary breast and ovarian cancer (HBOC) is estimated to represent 5-10% of all breast and ovarian cancer cases. Pathogenic germline variants in BRCA1 and BRCA2 account for 25% of familial cases. The identification of genetic defects in HBOC patients allows detection of carriers that can benefit from cancer risk management protocols, and predictive genetic testing to at-risk family members, after appropriate genetic counseling. Two female patients with a personal and family history of cancer were studied by next-generation sequencing (NGS). Methods: NGS using TruSight Cancer Panel (Illumina) followed by bioinformatic analysis of 18 genes associated with HBOC was performed. Pathogenic variants were confirmed by Sanger sequencing. Results: A rare event of double heterozigosity for pathogenic variants was identified in both patients: patient A was heterozygous for BRCA1:c.2037delinsCC, p.(Lys679Asn*4) and ATM:c.3802delG, p.(Val1268*) and patient B carried both BRCA2:c.6001dupT, p.(Ser2001Phefs*2) and ATM:3435_3436delTGinsA, p.(Asp1145Glufs*11). After genetic counseling, three relatives of patient A were analyzed: while one of her two healthy sons was heterozygous for the ATM variant, the other was a double heterozygote for BRCA1:c.2037delinsCC and ATM:c.3802delG; a female cousin, recently diagnosed with breast cancer, was a carrier of ATM:c.3802delG only. Conclusions: The identification of these two rare cases of double heterozigosity for pathogenic variants in BRCA1/BRCA2 and ATM genes, highlights the importance of using NGS-gene panel testing in HBOC. If molecular analysis had been restricted to BRCA genes only, the pathogenic ATM variants would have been missed in both families, depriving them of appropriate genetic counseling and cancer risk management.info:eu-repo/semantics/publishedVersio

De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands.status: publishe