@article {965, title = {A novel homozygous variant in results in a neurodevelopmental disorder and disrupts TRAPP complex function.}, journal = {J Med Genet}, year = {2020}, month = {2020 Aug 25}, abstract = {

BACKGROUND: Next-generation sequencing has facilitated the diagnosis of neurodevelopmental disorders with variable and non-specific clinical findings. Recently, a homozygous missense p.(Asp37Tyr) variant in a core subunit of TRAPP complexes which function as tethering factors during membrane trafficking, was reported in two unrelated individuals with neurodevelopmental delay, post-infectious encephalopathy-associated developmental arrest, tetraplegia and accompanying rhabdomyolysis.

METHODS: We performed whole genome sequencing on members of an Ashkenazi Jewish pedigree to identify the underlying genetic aetiology of global developmental delay/intellectual disability in three affected siblings. To assess the effect of the identified variant, we performed biochemical and cell biological functional studies on the TRAPPC2L protein.

RESULTS: A rare homozygous predicted deleterious missense variant, p.(Ala2Gly), in was identified in the affected siblings and it segregated with the neurodevelopmental phenotype within the family. Using a yeast two-hybrid assay and binding, we demonstrate that the p.(Ala2Gly) variant, but not the p.(Asp37Tyr) variant, disrupted the interaction between TRAPPC2L and another core TRAPP protein, TRAPPC6a. Size exclusion chromatography suggested that this variant affects the assembly of TRAPP complexes. Employing two different membrane trafficking assays using fibroblasts from one of the affected siblings, we found a delay in traffic into and out of the Golgi. Similar to the p.(Asp37Tyr) variant, the p.(Ala2Gly) variant resulted in an increase in the levels of active RAB11.

CONCLUSION: Our data fill in a gap in the knowledge of TRAPP architecture with TRAPPC2L interacting with TRAPPC6a, positioning it as a putative adaptor for other TRAPP subunits. Collectively, our findings support the pathogenicity of the p.(Ala2Gly) variant.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2020-107016}, author = {Al-Deri, Noraldin and Okur, Volkan and Ahimaz, Priyanka and Milev, Miroslav and Valivullah, Zaheer and Hagen, Jacob and Sheng, Yufeng and Chung, Wendy and Sacher, Michael and Ganapathi, Mythily} } @article {591, title = {De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment.}, journal = {Eur J Hum Genet}, volume = {27}, year = {2019}, month = {2019 Jul}, pages = {1081-1089}, abstract = {

Hexokinase 1 (HK1) phosphorylates glucose to glucose-6-phosphate, the first rate-limiting step in glycolysis. Homozygous and heterozygous variants in HK1 have been shown to cause autosomal recessive non-spherocytic hemolytic anemia, autosomal recessive Russe type hereditary motor and sensory neuropathy, and autosomal dominant retinitis pigmentosa (adRP). We report seven patients from six unrelated families with a neurodevelopmental disorder associated with developmental delay, intellectual disability, structural brain abnormality, and visual impairments in whom we identified four novel, de novo missense variants in the N-terminal half of HK1. Hexokinase activity in red blood cells of two patients was normal, suggesting that the disease mechanism is not due to loss of hexokinase enzymatic activity.

}, issn = {1476-5438}, doi = {10.1038/s41431-019-0366-9}, author = {Okur, Volkan and Cho, Megan T and van Wijk, Richard and van Oirschot, Brigitte and Picker, Jonathan and Coury, Stephanie A and Grange, Dorothy and Manwaring, Linda and Krantz, Ian and Muraresku, Colleen Clark and Hulick, Peter J and May, Holley and Pierce, Eric and Place, Emily and Bujakowska, Kinga and Telegrafi, Aida and Douglas, Ganka and Monaghan, Kristin G and Begtrup, Amber and Wilson, Ashley and Retterer, Kyle and Anyane-Yeboa, Kwame and Chung, Wendy K} } @article {727, title = {Homozygous noncanonical splice variant in in two siblings with multiple congenital anomalies and global developmental delay.}, journal = {Cold Spring Harb Mol Case Stud}, volume = {5}, year = {2019}, month = {2019 Jun}, abstract = {

Two siblings, one male and one female, ages 6 and 13 yr old, have similar clinical features of global developmental delay, multiple congenital anomalies affecting the cardiac, genitourinary, and skeletal systems, and abnormal eye movements. Whole-genome sequencing revealed a homozygous splice variant (NM_014462.3:c.231+4A>C) in that segregated with the phenotype in the family. LSM1 has a role in pre-mRNA splicing and degradation. Expression studies revealed absence of expression of the canonical isoform in the affected individuals. The knockout mice have a partially overlapping phenotype that affects the brain, heart, and eye. To our knowledge, has not been associated with any human disorder; however, the tissue expression pattern, gene constraint, and the similarity of the phenotype in our patients and the knockout mice models suggest it has a role in the development of multiple organ systems in humans.

}, issn = {2373-2873}, doi = {10.1101/mcs.a004101}, author = {Okur, Volkan and LeDuc, Charles A and Guzman, Edwin and Valivullah, Zaheer M and Anyane-Yeboa, Kwame and Chung, Wendy K} }