Biallelic MFSD2A variants associated with congenital microcephaly, developmental delay, and recognizable neuroimaging features


Major Facilitator Superfamily Domain containing 2a (MFSD2A) is an essential endothelial lipid transporter at the blood-brain barrier. Biallelic variants affecting function in MFSD2A cause autosomal recessive primary microcephaly 15 (MCPH15, OMIM# 616486). We sought to expand our knowledge of the phenotypic spectrum of MCPH15 and demonstrate the underlying mechanism of inactivation of the MFSD2A transporter. We carried out detailed analysis of the clinical and neuroradiological features of a series of 27 MCPH15 cases, including eight new individuals from seven unrelated families. Genetic investigation was performed through exome sequencing (ES). Structural insights on the human Mfsd2a model and in-vitro biochemical assays were used to investigate the functional impact of the identified variants. All patients had primary microcephaly and severe developmental delay. Brain MRI showed variable degrees of white matter reduction, ventricular enlargement, callosal hypodysgenesis, and pontine and vermian hypoplasia. ES led to the identification of six novel biallelic MFSD2A variants (NG_053084.1, NM_032793.5: c.556+1G>A, c.748G>T; p.(Val250Phe), c.750_753del; p.(Cys251SerfsTer3), c.977G>A; p.(Arg326His), c.1386_1435del; p.(Gln462HisfsTer17), and c.1478C>T; p.(Pro493Leu)) and two recurrent variants (NM_032793.5: c.593C>T; p.(Thr198Met) and c.476C>T; p.(Thr159Met)). All these variants and the previously reported NM_032793.5: c.490C>A; p.(Pro164Thr) resulted in either reduced MFSD2A expression and/or transport activity. Our study further delineates the phenotypic spectrum of MCPH15, refining its clinical and neuroradiological characterization and supporting that MFSD2A deficiency causes early prenatal brain developmental disruption. We also show that poor MFSD2A expression despite normal transporter activity is a relevant pathomechanism in MCPH15.

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Fig. 1: Clinical characterization, neuroimaging features, genetic findings and predicted consequences of MFSD2A variants.
Fig. 2: Biochemical analysis of Mfsd2a variants.


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The work was supported in part by National Research Foundation and Ministry of Health grants, Singapore; by the Biomedical Research Council of A*STAR; by March of Dimes Research Grant; as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.


National Research Foundation grants, Singapore NRF2016NRF-NRFI001-15 and OF-IRG MOH-000217 (to DLS); Biomedical Research Council of A*STAR (to HF); The MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA), March of Dimes USA (to MCM), The R01 RNS107428A by the National Institute of Neurological Disorders and Stroke/National Institutes of Health (NINDS/NIH).

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Correspondence to Reza Maroofian or David L. Silver.

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Scala, M., Chua, G.L., Chin, C.F. et al. Biallelic MFSD2A variants associated with congenital microcephaly, developmental delay, and recognizable neuroimaging features. Eur J Hum Genet 28, 1509–1519 (2020).

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