Though Langer-Giedion Syndrome (LGS) is described as a chromosomal disorder caused by a deletion at 8q23q24 which encompasses genes TRPS1, EXT1, and RAD21, there remains to be a strong genotype-phenotype correlation because molecular genetic testing of LGS patients is not often reported in literature. The authors report two unrelated patients with LGS who have the 8q23q24 deletion, while also reviewing 10 other patients from existing literature. Phenotypic characteristics included exostoses, sparse hair, thickness of eyebrows, shortening of metacarpal/metatarsal bones, thick nasal septum, and hip dysplasia are just some of the phenotypes typical of LGS patients found in all 14 cases. Patient 1 and 2 in this study showed interstitial deletions of 8.3 Mb and 3.2 Mb in chromosome 8q, respectively; additionally, a 2.1 Mb duplication was detected in chromosome 15q for Patient 1. Patient 2 presents the smallest deleted segment in this report and still shows a typical clinical phenotype of LGS; thus, this may be the minimal deletion region for the syndrome. Within this minimal region lies the genes TRPS1, EXT1, and RAD21. The authors found TRPS1 to be pathogenic and haploinsufficient due to its involvement in chondrocyte differentiation. All patients in the review, including the authors’ two patients, showed the whole deletion of EXT1 and the development of exostoses, suggesting that exostoses are more likely derived from the EXT1 gene. RAD21 is located between the prior two genes, and because it is deleted with them, it is difficult to assess its true genotype-phenotype correlation. In addition to the genes within the minimal deleted region, the authors’ pathogenic analysis identified the deletion of CSMD3 gene as likely pathogenic. Previously it has been linked to intellectual disabilities in LGS (7/11), supporting the idea that we cannot rule out the involvement of other genes in LGS phenotype.
Favilla et al. “Minimal Critical Region and Genes for a Typical Presentation of Langer-Giedion Syndrome”. “Cytogenetic and Genome Research” 2022, v. 162 (1-2), 46-54
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