Novel Mutations in the Asparagine Synthetase Gene () Associated With Microcephaly.

Microcephaly is a devastating condition defined by a small head and small brain compared to the age- and sex-matched population. Mutations in a number of different genes causative for microcephaly have been identified, e.g., , and . Recently, mutations in the gene encoding the enzyme asparagine synthetase () were associated to microcephaly and so far 24 different mutations in causing microcephaly have been described. In a family with two affected girls, we identified novel compound heterozygous variants in (c.1165G > C, p.E389Q and c.601delA, p.M201Wfs28). The first mutation (E389Q) is a missense mutation resulting in the replacement of a glutamate residue evolutionary conserved from to by glutamine. Protein modeling based on the known crystal structure of ASNS of predicted a destabilization of the protein by E389Q. The second mutation (p.M201Wfs28) results in a premature stop codon after amino acid 227, thereby truncating more than half of the protein. The novel variants expand the growing list of microcephaly causing mutations in .