Improving the diagnosis of cobalamin and related defects by genomic analysis, plus functional and structural assessment of novel variants

Abstract

[...]MMAA is the gene associated with complementation group cblA defects (MIM# 607481). The diagnosis of an intracellular cobalamin metabolism disorder in a symptomatic individual is based on both clinical suspicion and biochemical analyses [1, 21]. Since expanded newborn screening potentially allows early detection of certain disorders of intracellular cobalamin metabolism, some affected individuals may be diagnosed prior to the onset of clinical symptoms. [...]Ile312 was involved in a dense network of residue interactions, although no close contact (<5Angs) with the residues from the functional “phosphate shuttle” loop was observed. The sensitivity and specificity of the method appeared to be very good and the results reproducible (several mutations were detected in more than one unrelated mutant allele i.e., c.271dupA in MMACHC, c.671_678dupAATTTATG in MUT, c.748C > T in MMADHC etc.). [...]even though the use of smaller, specific panels is recommended [36] so that secondary incidental findings are avoided, the present work shows clinical exome sequencing to be successful.