Genetic factors in lissencephaly syndromes: a review

Lissencephaly is a sign of various genetic and non-genetic conditions and a constant feature in the so-called lissencephaly syndromes. Type I lissencephaly in the Miller-Dieker syndrome (MDS) and the isolated lissencephaly sequence (ILS) is differentiated from type II lissencephaly in the Walker-Warburg (hydrocephalus, agyria, retinal dysplasia with or without encephalocele, HARD +/- E) syndrome and related conditions (e.g. muscle-eye-brain syndrome). In about 90% of patients with MDS structural defects have been confirmed in the short arm of chromosome 17 (p13.3), detectable by classical cytogenetic methods, fluorescence in situ hybridisation (FISH), or molecular genetic techniques. The identification of unbalanced inversions and translocations is of particular importance because of the risk of their recurrence, while deletions and ring chromosomes are mainly sporadic. Recently, submicroscopic deletions have also been reported in ILS, providing evidence that lissencephaly in MDS and ILS is caused by deletions of the same gene(s) in 17p13.3 and that MDS may be considered to be a "contiguous gene syndrome." Syndromes featuring lissencephaly type II (HARD +/- E and related conditions) are most probably autosomal-recessively inherited. Neither the location of the genes involved nor the nature of the mutations are known at present. It is also unknown whether HARD +/- E and muscle-eye-brain syndrome are allelic.