Teixeira Bernardo De Sousa, SA; (2014) Clinical and Molecular Characterisation of Rare Genetic Syndromes with Unknown Aetiology. Doctoral thesis , UCL (University College London).

Abstract

This project aimed to clinically characterise phenotypes with unknown genetic aetiology and proceed with customised gene identification strategies in selected cases/families. A systematic analysis of 116 medical records of undiagnosed cases observed at the Medical Genetics Department of the Coimbra Paediatric Hospital, corresponding to 52 families, was performed in order to identify phenotypes to better describe and identify their aetiologies. Thirty-three families were observed in the clinic to allow for careful examination and detailed phenotyping. In five of the observed families, likely previously clinically unrecognised syndromes were identified. Eighteen families with the clearest or distinct phenotype, evidence of consanguinity, or the most available family members, and therefore the highest chance of finding the mutated gene, were then selected for further research. In four of the selected cases, the chosen gene identification strategies were completed during this project. In one autosomal recessive family, no variants considered to be likely causative were identified and in the other three families, X¬exome sequencing revealed novel, likely pathogenic, variants in known X-linked intellectual disability genes: HUWE 1, SLC16A2 and PAK3. Whole-exome sequencing is ongoing on 6 families and the remaining 8 families were not possible to be studied. In addition to the familial cases, one sporadic case with the diagnosis of Lenz-Majewski syndrome was observed. Five other cases were subsequently recruited worldwide and a gene identification strategy, consisting of whole exome-sequencing and selecting variants according to the predicted genetic aetiology model, was implemented. We identified causative de novo missense heterozygous mutations in PTDSS1 gene, which encodes for phosphatidylserine synthase 1. We carried out further studies in patient fibroblasts and zebrafish embryos which led us to the conclusion that these mutations have a gain-of-function effect, associated with regulatory dysfunction. Another condition, for which I had a particular interest, was Nicolaides-Baraitser syndrome. Initial work was to clinically describe 23 cases, allowing the syndrome to be delineated and established as a discrete entity. Subsequently, work was to collect further data and DNA samples with the aim of identifying its causative gene. Using whole exome sequencing, dominant-negative de novo heterozygous mutations in SMARCA2, encoding one of two alternating catalytic subunits of the chromatin remodeller complex BAF, were identified in 37/44 cases. No definite genotype-phenotype correlations were established.

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