2. Academic Validation
  3. Biallelic MFSD2A variants associated with congenital microcephaly, developmental delay, and recognizable neuroimaging features

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

  • Eur J Hum Genet. 2020 Nov;28(11):1509-1519. doi: 10.1038/s41431-020-0669-x.
Marcello Scala # 1 2 3,  Geok Lin Chua # 4,  Cheen Fei Chin 4,  Hessa S Alsaif 5,  Artem Borovikov 6,  Saima Riazuddin 7,  Sheikh Riazuddin 8 9,  M Chiara Manzini 10,  Mariasavina Severino 11,  Alvin Kuk 4,  Hao Fan 12 13 14,  Yalda Jamshidi 15,  Mehran Beiraghi Toosi 16,  Mohammad Doosti 16,  Ehsan Ghayoor Karimiani 16,  Vincenzo Salpietro 1 2 3,  Elena Dadali 6,  Galina Baydakova 6,  Fedor Konovalov 17 18,  Ekaterina Lozier 17 18,  Emer O'Connor 1,  Yasser Sabr 19,  Abdullah Alfaifi 20,  Farah Ashrafzadeh 21,  Pasquale Striano 2 3,  Federico Zara 2 22,  Fowzan S Alkuraya 23 24,  Henry Houlden 1,  Reza Maroofian 25 26,  David L Silver 27
Affiliations

Affiliations

  • 1 Department of Neuromuscular Disorders, Institute of Neurology, University College London, London, UK.
  • 2 Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
  • 3 Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
  • 4 Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Singapore.
  • 5 Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
  • 6 Research Centre for Medical Genetics, Moscow, Russia.
  • 7 Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, 21201, USA.
  • 8 Center for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad, Pakistan.
  • 9 National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, 53700, Pakistan.
  • 10 Department of Neuroscience and Cell Biology and Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA.
  • 11 Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
  • 12 Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis St., Matrix No. 07-01, Singapore, 138671, Singapore.
  • 13 Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore.
  • 14 Centre for Computational Biology, DUKE-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
  • 15 Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK.
  • 16 Department of pediatric diseases, Faculty of medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
  • 17 Independent Clinical Bioinformatics Laboratory, Moscow, Russia.
  • 18 Genomed Ltd., Moscow, Russia.
  • 19 Department of Obstetrics and Gynecology, King Saudi University, Riyadh, Saudi Arabia.
  • 20 Pediatrics Department, Security Forces Hospital, Riyadh, Saudi Arabia.
  • 21 Department of Pediatric Diseases, Mashhad University of Medical Sciences, Mashhad, Iran.
  • 22 Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, Genova, Italy.
  • 23 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 24 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
  • 25 Department of Neuromuscular Disorders, Institute of Neurology, University College London, London, UK. [email protected].
  • 26 Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK. [email protected].
  • 27 Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Singapore. [email protected].
  • # Contributed equally.
PMID: 32572202 DOI: 10.1038/s41431-020-0669-x
Abstract

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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