Functional Characterization of Variants in : Report of Three New Individuals With Alazami Syndrome and a Literature Review.

Biallelic pathogenic variants in result in Alazami syndrome, which is characterized by global developmental delay, cognitive dysfunction, and dysmorphic features. Cardiac and skeletal phenotypes are reported in about 30% of individuals. We report three new individuals with Alazami syndrome and functional characterization of variants in this study. We reviewed electronic patient charts. We applied the American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant classification algorithms. We performed a 3D protein modeling tool for in silico prediction and functional characterization of variants using qPCR gene expression experiments. We reviewed the medical literature for Alazami syndrome and . We report three individuals from two unrelated families with characteristic phenotypes suggestive of Alazami syndrome. We identified a homozygous novel missense likely pathogenic variant (p.Asp54Val) in Family 1 and a homozygous novel pathogenic variant (p.Lys219Glu∗) in Family 2 using clinical exome sequencing. 3D protein modeling showed large structural changes for both variants compared to wildtype. The functional characterization showed a statistically significant difference in LARP7 expression between affected individuals and wildtype control. We report phenotypic variability within the same family that the cardiac phenotype was only present in Family 1, Case 2. There were < 60 individuals with Alazami syndrome reported to date. We report three new individuals with Alazami syndrome and two novel variants in . We report the first missense variant associated with Alazami syndrome. We report the protein 3D structure of variants. We show a relationship between the p.Asp54Val variant and LARP7 expression levels. We think that this could be due to abnormal RNA binding of LARP7 as per the 3D protein modeling prediction tool.