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

Marcello Scala, Geok Lin Chua, Cheen Fei Chin, Hessa S Alsaif, Artem Borovikov, Saima Riazuddin, Sheikh Riazuddin, M Chiara Manzini, Mariasavina Severino, Alvin Kuk, Hao Fan, Yalda Jamshidi, Mehran Beiraghi Toosi, Mohammad Doosti, Ehsan Ghayoor Karimiani, Vincenzo Salpietro, Elena Dadali, Galina Baydakova, Fedor Konovalov, Ekaterina LozierEmer O'Connor, Yasser Sabr, Abdullah Alfaifi, Farah Ashrafzadeh, Pasquale Striano, Federico Zara, Fowzan S Alkuraya, Henry Houlden, Reza Maroofian, David L Silver

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1509-1519
Number of pages11
JournalEuropean Journal of Human Genetics
Issue number11
Publication statusPublished - Nov 2020


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