No abstract

Methionine synthase deficiency (cblG complementation group) is a rare inborn error of metabolism affecting the homocysteine re-methylation pathway. It leads to a biochemical phenotype of hyperhomocysteinemia and hypomethioninemia. The clinical presentation of cblG is variable, ranging from seizures, encephalopathy, macrocytic anemia, hypotonia, and feeding difficulties in the neonatal period to onset of psychiatric symptoms or acute neurologic

Purpose: Brain malformations caused by 17p13.3 deletions include lissencephaly with deletions of the larger Miller-Dieker syndrome region or smaller deletions of only PAFAH1B1 , white matter changes, and a distinct syndrome due to deletions including YWHAE and CRK but sparing PAFAH1B1. We sought to understand the significance of 17p13.3 deletions between the YWHAE / CRK and PAFAH1B1 loci. Methods: We analyzed the clinical features of six individuals from five families with 17p13.3 deletions between and not including YWHAE / CRK and PAFAH1B1 identified among individuals undergoing clinical chromosomal microarray testing or research genome sequencing. Results: Five individuals from four families have multi-focal white matter lesions while a sixth had a normal MRI. A combination of our individuals and a review of those in the literature with white matter changes and deletions in this chromosomal region narrows the overlapping region for this brain phenotype to ~345 kb, including 11 RefSeq genes, with RTN4RL1 haploinsufficiency as the best candidate for causing this phenotype. Conclusion: While previous literature has hypothesized dysmorphic features and white matter changes related to YWHAE , our cohort contributes evidence to the presence of additional genetic changes within 17p13.3 required for proper brain development.

No abstract