Submission Details

MBOAT7 encodes an enzyme that regulates arachidonic acid incorporation in lysophosphatidylinositol. MBOAT7 was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2016 (Johansen et al., PMID: 27616480). Probands with variants in MBOAT7 frequently have the phenotypic features of moderate to severe developmental delay, absent speech, infant-onset epilepsy, truncal hypotonia and autistic features. Eight variants (nonsense, frameshift and splice-site) that have been reported in ten probands in four publications (PMIDs: 27616480, 32645526, 31282596, 3335874) are included in this curation. All variants described were homozygous, and one variant, c.758_778del, was reported in three unrelated families. More evidence is available in the literature (PMID: 30701556), but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported as loss of function (PMID: 27616480). This gene-disease relationship is also supported by a knock-out Mboat7 mouse model (PMID: 23097495). This model showed complete ablation of Mboat7 enzyme activity, an absence of the protein in brain tissue, and displayed atrophy of the cerebral cortex, disordered cortical lamination, and delayed neuron migration. Additionally, expression of two disease-related variants in HepG2 cells (p.(Tyr354*) and p.(Leu379Trpfs*9)) showed absent Mboat7 protein on western blot (PMID: 32645526). In summary, there is definitive evidence supporting the relationship between MBOAT7 and autosomal recessive complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on the meeting date November 21, 2023 (SOP Version 10).