Minimal Critical Region and Genes for a Typical Presentation of Langer-Giedion Syndrome

Abstract

Langer-Giedion syndrome (LGS) is caused by a contiguous deletion at 8q23q24, characterized by exostoses, facial, ectodermal, and skeletal anomalies, and, occasionally, intellectual disability. LGS patients have been diagnosed clinically or by routine cytogenetic techniques, hampering the definition of an accurate genotype-phenotype correlation for the syndrome. We report two unrelated patients with 8q23q24 deletions, characterized by cytogenomic techniques, with one of them, to our knowledge, carrying the smallest deletion reported in classic LGS cases. We assessed the pathogenicity of the deletion of genes within the 8q23q24 region and reviewed other molecularly confirmed cases from the literature. Our findings suggest a 3.2-Mb critical region for a typical presentation of the syndrome, emphasizing the contribution of the <i>TRPS1</i>, <i>RAD21</i>, and <i>EXT1</i> genes’ haploinsufficiency, and facial dysmorphisms as well as bone anomalies as the most frequent features among patients with LGS. We also suggest a possible role for the <i>CSMD3</i> gene, whose deletion seems to contribute to central nervous system anomalies. Since studies performing such correlation for LGS patients are limited, our data contribute to improving the ge­notype-phenotype characterization for LGS patients.

The Clinical and Molecular Spectrum of Trichorhinophalangeal Syndrome Types I and II in a Turkish Cohort Involving 22 Patients

“…Genotype–phenotype studies in TRPS II have shown no correlation between the size of the deleted segment and the severity of disease manifestations. 16 , 17 Correspondingly, among the 3 TRPS II patients in our cohort, P6 had the second largest deletion despite having the most severe phenotype with severe microcephaly, developmental delay, short stature, and oligodactyly. Of our 3 patients with TRPS II, 2 patients had deletions of the entire EXT1 gene, and 1 patient (P6) had a deletion in EXT1 beginning from the second exon.…”

“… 18 , 19 A very recent genotype–phenotype study reported that the minimal critical region responsible for the classical phenotypic features of TRPS II is a region of approximately 3 Mb in size, encompassing the TRPS1 - EXT1 interval. 17 However, with the addition of our TRPS II patient with the partial EXT1 deletion, the minimal critical region for TRPS II has proven to be smaller, since the clinical findings in this patient occurred due to the haploinsufficiency of the EXT1 gene partially rather than the entire gene.…”