@article {949, title = {A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome.}, journal = {Eur J Hum Genet}, volume = {29}, year = {2021}, month = {2021 Feb}, pages = {271-279}, abstract = {

Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering. TRAPPC4 was recently implicated in a recessive neurodevelopmental condition in four unrelated families due to a shared c.454+3A>G splice variant. Here, we report 23 patients from 17 independent families with an early-infantile-onset neurodegenerative presentation, where we also identified the homozygous variant hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G) in TRAPPC4 through exome or genome sequencing. No other clinically relevant TRAPPC4 variants were identified among any of over 10,000 patients with neurodevelopmental conditions. We found the carrier frequency of TRAPPC4 c.454+3A>G was 2.4-5.4 per 10,000 healthy individuals. Affected individuals with the homozygous TRAPPC4 c.454+3A>G variant showed profound psychomotor delay, developmental regression, early-onset epilepsy, microcephaly and progressive spastic tetraplegia. Based upon RNA sequencing, the variant resulted in partial exon 3 skipping and generation of an aberrant transcript owing to use of a downstream cryptic splice donor site, predicting a premature stop codon and nonsense mediated decay. These data confirm the pathogenicity of the TRAPPC4 c.454+3A>G variant, and refine the clinical presentation of TRAPPC4-related encephalopathy.

}, issn = {1476-5438}, doi = {10.1038/s41431-020-00717-5}, author = {Ghosh, Shereen G and Scala, Marcello and Beetz, Christian and Helman, Guy and Stanley, Valentina and Yang, Xiaoxu and Breuss, Martin W and Mazaheri, Neda and Selim, Laila and Hadipour, Fatemeh and Pais, Lynn and Stutterd, Chloe A and Karageorgou, Vasiliki and Begtrup, Amber and Crunk, Amy and Juusola, Jane and Willaert, Rebecca and Flore, Leigh A and Kennelly, Kelly and Spencer, Christopher and Brown, Martha and Trapane, Pamela and Hurst, Anna C E and Lane Rutledge, S and Goodloe, Dana H and McDonald, Marie T and Shashi, Vandana and Schoch, Kelly and Tomoum, Hoda and Zaitoun, Raghda and Hadipour, Zahra and Galehdari, Hamid and Pagnamenta, Alistair T and Mojarrad, Majid and Sedaghat, Alireza and Dias, Patr{\'\i}cia and Quintas, Sofia and Eslahi, Atiyeh and Shariati, Gholamreza and Bauer, Peter and Simons, Cas and Houlden, Henry and Issa, Mahmoud Y and Zaki, MAH S and Maroofian, Reza and Gleeson, Joseph G} } @article {968, title = {Evaluating systematic reanalysis of clinical genomic data in rare disease from single center experience and literature review.}, journal = {Mol Genet Genomic Med}, volume = {8}, year = {2020}, month = {2020 11}, pages = {e1508}, abstract = {

BACKGROUND: Our primary aim was to evaluate the systematic reanalysis of singleton exome sequencing (ES) data for unsolved cases referred for any indication. A secondary objective was to undertake a literature review of studies examining the reanalysis of genomic data from unsolved cases.

METHODS: We examined data from 58 unsolved cases referred between June 2016 and March 2017. First reanalysis at 4-13~months after the initial report considered genes newly associated with disease since the original analysis; second reanalysis at 9-18~months considered all disease-associated genes. At 25-34~months we reviewed all cases and the strategies which solved them.

RESULTS: Reanalysis of existing ES data alone at two timepoints did not yield new diagnoses. Over the same timeframe, 10 new diagnoses were obtained (17\%) from additional strategies, such as microarray detection of copy number variation, repeat sequencing to improve coverage, and trio sequencing. Twenty-seven peer-reviewed articles were identified on the literature review, with a median new diagnosis rate via reanalysis of 15\% and median reanalysis timeframe of 22~months.

CONCLUSION: Our findings suggest that an interval of greater than 18~months from the original report may be optimal for reanalysis. We also recommend a multi-faceted strategy for cases remaining unsolved after singleton ES.

}, issn = {2324-9269}, doi = {10.1002/mgg3.1508}, author = {Tan, Natalie B and Stapleton, Rachel and Stark, Zornitza and Delatycki, Martin B and Yeung, Alison and Hunter, Matthew F and Amor, David J and Brown, Natasha J and Stutterd, Chloe A and McGillivray, George and Yap, Patrick and Regan, Matthew and Chong, Belinda and Fanjul Fernandez, Miriam and Marum, Justine and Phelan, Dean and Pais, Lynn S and White, Susan M and Lunke, Sebastian and Tan, Tiong Y} } @article {582, title = {Cerebral hypomyelination associated with biallelic variants of FIG4.}, journal = {Hum Mutat}, volume = {40}, year = {2019}, month = {2019 05}, pages = {619-630}, abstract = {

The lipid phosphatase gene FIG4 is responsible for Yunis-Var{\'o}n syndrome and Charcot-Marie-Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G > A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read-through from exon 20 into intron 20 and truncation of the final 115 C-terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defects in the FIG4 null mouse and the known role of FIG4 in oligodendrocyte maturation. The families described here the expanded clinical spectrum of FIG4 deficiency to include leukoencephalopathy.

}, issn = {1098-1004}, doi = {10.1002/humu.23720}, author = {Lenk, Guy M and Berry, Ian R and Stutterd, Chloe A and Blyth, Moira and Green, Lydia and Vadlamani, Gayatri and Warren, Daniel and Craven, Ian and Fanjul-Fernandez, Miriam and Rodriguez-Casero, Victoria and Lockhart, Paul J and Vanderver, Adeline and Simons, Cas and Gibb, Susan and Sadedin, Simon and White, Susan M and Christodoulou, John and Skibina, Olga and Ruddle, Jonathan and Tan, Tiong Y and Leventer, Richard J and Livingston, John H and Meisler, Miriam H} }