Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165

Three patients belonging to two families presented with a psychomotor-dysmorphism syndrome including postnatal growth deficiency and major spondylo-, epi-, and metaphyseal skeletal involvement. Other features were muscular hypotrophy, fat excess, partial growth hormone deficiency, and, in two of the three patients, episodes of unexplained fever. Additional investigations showed mild to moderate increases of serum transaminases (particularly of aspartate transaminase (AST)), creatine kinase (CK), and lactate dehydrogenase (LDH), as well as decreased coagulation factors VIII, IX, XI, and protein C. Diagnostic work-up revealed a type 2 serum transferrin isoelectrofocusing (IEF) pattern and a cathodal shift on apolipoprotein C-III IEF pointing to a combined N- and O-glycosylation defect. Known glycosylation disorders with similar N-glycan structures lacking galactose and sialic acid were excluded. Through a combination of homozygosity mapping and expression profiling, a deep intronic homozygous mutation (c.792 + 182G>A) was found in TMEM165 (TPARL) in the three patients. TMEM165 is a gene of unknown function, possibly involved in Golgi proton/calcium transport. Here we present a detailed clinical description of the three patients with this mutation. The TMEM165 deficiency represents a novel type of CDG (TMEM165-CDG). This disorder enlarges the group of CDG caused by deficiencies in proteins that are not specifically involved in glycosylation but that have functions in the organization and homeostasis of the intracellular compartments and the secretory pathway, like COG-CDG and ATP6V0A2-CDG.status: publishe