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01.12.2017 | Case report | Ausgabe 1/2017 Open Access

BMC Medical Genetics 1/2017

Severe congenital microcephaly with AP4M1 mutation, a case report

BMC Medical Genetics > Ausgabe 1/2017
Sarah Duerinckx, Helene Verhelst, Camille Perazzolo, Philippe David, Laurence Desmyter, Isabelle Pirson, Marc Abramowicz
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Electronic supplementary material

The online version of this article (doi:10.​1186/​s12881-017-0412-9) contains supplementary material, which is available to authorized users.



Autosomal recessive defects of either the B1, E1, M1 or S1 subunit of the Adaptor Protein complex-4 (AP4) are characterized by developmental delay, severe intellectual disability, spasticity, and occasionally mild to moderate microcephaly of essentially postnatal onset.

Case presentation

We report on a patient with severe microcephaly of prenatal onset, and progressive spasticity, developmental delay, and severe intellectual deficiency. Exome sequencing showed a homozygous mutation in AP4M1, causing the replacement of an arginine by a stop codon at position 338 of the protein (p.Arg338X). The premature stop codon truncates the Mu homology domain of AP4M1, with predicted loss of function. Exome analysis also showed heterozygous variants in three genes, ATR, MCPH1 and BLM, which are known causes of autosomal recessive primary microcephaly.


Our findings expand the AP4M1 phenotype to severe microcephaly of prenatal onset, and more generally suggest that the AP4 defect might share mechanisms of prenatal neuronal depletion with other genetic defects of brain development causing congenital, primary microcephaly.
Additional file 1: 68 primary microcephaly-associated genes used for initial analysis of whole exome sequencing data. (PDF 34 kb)
Additional file 2: Clinical features in reported cases of AP4 defects and in the present proband. (PDF 76 kb)
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