Microphthalmia with linear skin defects (MLS) syndrome: Clinical, cytogenetic, and molecular characterization of 11 cases

Abstract

The microphthalmia with linear skin defects (MLS) syndrome (MIM 309801) is a severe and rare developmental disorder, which is inherited as an X-linked dominant trait with male lethality. In the vast majority of patients, this syndrome is associated with terminal deletion of the Xp22.3 region. Thirty-five cases have been described to date in the literature since the first description of the syndrome in the early 1990s. We now report on the clinical, cytogenetic, and molecular characterization of 11 patients, 7 of whom have not been described previously. Seven of these patients have chromosomal abnormalities of the short arm of the X-chromosome, which were characterized and defined by fluorescence in situ hybridization (FISH) analysis. Intriguingly, one of the patients displays an interstitial Xp22.3 deletion, which to the best of our knowledge is the first reported for this condition. Finally we report on the identification and molecular characterization of four cases with clinical features of MLS but apparently normal karyotypes, verified by FISH analysis using genomic clones spanning the MLS minimal critical region, and with genome-wide analysis using a 1 Mb resolution BAC microarray. These patients made it possible to undertake mutation screening of candidate genes and may prove critical for the identification of the gene responsible for this challenging and intriguing genetic disease.

Dosage compensation of the mammalian X chromosome influences the phenotypic variability of X-linked dominant male-lethal disorders

“…Additional features include agenesis of the corpus callosum, sclerocornea, chorioretinal abnormalities, infantile seizures, congenital heart defects, and mental retardation. In the majority of cases, patients carry deletions or unbalanced translocations involving the Xp22.3 region resulting in segmental monosomy of this chromosome 18. Although most patients display the classical phenotype of MLS, a high phenotypic variability, not correlated to the extent of the deleted region, has been reported.…”

X-inactivation and human disease: X-linked dominant male-lethal disorders

“…Additional features include sclerocornea, corneal opacities, agenesis of the corpus callosum, ventriculomegaly, microcephaly, mental retardation, infantile seizures and, more rarely, cardiac anomalies. MLS is predominantly observed in patients with deletions and unbalanced translocations that involve the Xp22.3 region and that result in monosomy for this region [24]. Aicardi and Goltz syndromes share some similarities with MLS syndrome, and a few reports have described MLS patients with Xp22 deletions as possibly having Aicardi or Goltz syndromes.…”

Meis1 coordinates a network of genes implicated in eye development and microphthalmia

“…Cases of anophthalmia and microphthalmia have been associated with homozygous and heterozygous mutations in genes at the core of forebrain regulatory networks (Beccari et al, 2013), such as the transcription factors (TFs) SOX2 (Fantes et al, 2003), OTX2 (Ragge et al, 2005), PAX6 (Glaser et al, 1994), VSX2 (CHX10) (Ferda Percin et al, 2000), RAX (Voronina et al, 2004), FOXE3 (Reis et al, 2010) and perhaps SIX6 (Gallardo et al, 2004); in key components of cell to cell communication, including SHH (Schimmenti et al, 2003) and BMP4 (Reis et al, 2011); or in genes involved in retinal progenitor proliferation and survival such as STRA6 (Pasutto et al, 2007;White et al, 2008), BCOR (Ng et al, 2004), HCCS (Indrieri et al, 2013;Morleo et al, 2005) and SMOC1 (Abouzeid et al, 2011;Okada et al, 2011). Yet, only a minor proportion of patients receive an accurate molecular diagnosis of the pathogenesis of their ocular malformation Williamson and FitzPatrick, 2014), indicating that additional causative genes need to be identified.…”