Novel Pathogenetic Variants in PTHLH and TRPS1 Genes Causing Syndromic Brachydactyly

Abstract

Skeletal disorders, including both isolated and syndromic brachydactyly type E, derive from genetic defects affecting the fine tuning of the network of pathways involved in skeletogenesis and growth-plate development. Alterations of different genes of this network may result in overlapping phenotypes, as exemplified by disorders due to the impairment of the parathyroid hormone/parathyroid hormone-related protein pathway, and obtaining a correct diagnosis is sometimes challenging without a genetic confirmation. Five patients with Albright's hereditary osteodystrophy (AHO)-like skeletal malformations without a clear clinical diagnosis were analyzed by whole-exome sequencing (WES) and novel potentially pathogenic variants in parathyroid hormone like hormone (PTHLH) (BDE with short stature [BDE2]) and TRPS1 (tricho-rhino-phalangeal syndrome [TRPS]) were discovered. The pathogenic impact of these variants was confirmed by in vitro functional studies. This study expands the spectrum of genetic defects associated with BDE2 and TRPS and demonstrates the pathogenicity of TRPS1 missense variants located outside both the nuclear localization signal and the GATA ((A/T)GATA(A/G)-binding zinc-containing domain) and Ikaros-like binding domains. Unfortunately, we could not find distinctive phenotypic features that might have led to an earlier clinical diagnosis, further highlighting the high degree of overlap among skeletal syndromes associated with brachydactyly and AHO-like features, and the need for a close interdisciplinary workout in these rare patients.

A novel heterozygous mutation in PTHLH causing autosomal dominant brachydactyly type E complicated with short stature

“…Meanwhile, the patient II2 only had short fourth metacarpals in both hands. Our gathered data also showed that all the c.146dupA mutation carried individuals had short stature (−2 SD), including II2, III6, III16, III17, IV11, but the unaffected members in the pedigree had normal height, which was consistent with the previous literatures manifested that most affected individuals with PTHLH mutations had short stature (Elli et al., 2021 ; Klopocki et al., 2010 ; Thomas‐Teinturier et al., 2016 ). The short height of the affected individuals was probably caused by the premature closure of growth plate (Karaplis et al., 1994 ).…”

“…( 2010 ) identified p.L44P, p.L60P, p.K120*, and p.*178 W firstly in 2010 and proposed that loss‐of‐function mutations in PTHLH caused BDE with short stature. Subsequently, p.L15R, p.R56*, p.N87Tfs*18, p.R57*, p.Met1?, and p.E100Gfs*5 mutation in exons were identified (Bae et al., 2018 ; Elli et al., 2021 ; Jamsheer et al., 2016 ; Pereda et al., 2017 ; Wang et al., 2015 ). Additionally, two intragenetic novel alterations involving intron (c.101 + 3delAAGT, c.47_101 + 73del128) were also identified (Thomas‐Teinturier et al., 2016 ).…”

“…While Pereda et al (2017) illustrated shortening of all the metacarpals and shortening of third, fourth, and fifth metatarsals. The patients illustrated by Elli et al (2021) manifested shortening of third, fourth, and fifth metacarpals and, additionally, third and fourth metatarsals and second, third, fourth, and fifth phalanges, associated with short stature. In our study, although all the patients carried the same mutation, the phenotype was not consistent which further signified the intrafamilial variability of BDE.…”

A novel mutation in PTHLH in a family with a variable phenotype with brachydactyly, short stature, oligodontia and developmental delay

“…To date, twelve PTHLH mutations ( Bae et al, 2018 ; Elli et al, 2022 ; Fu et al, 2019 ; Jamsheer et al, 2016 ; Klopocki et al, 2010 ; Pereda et al, 2017 ; Reyes et al, 2019 ; Thomas-Teinturier et al, 2016 ; Wang et al, 2015 ), two families with PTHLH deletions ( Huang et al, 2019 ; Klopocki et al, 2010 ) and two families with balanced translocations leading to repression of PTHLH ( Maass et al, 2012 ; Maass et al, 2010 ) causing BDE have been reported to our knowledge (see Table 2 ). In 2010, Klopocki et al reported the first 5 unrelated families with gene defects in PTHLH .…”

Copy Number Variation and Osteoporosis

“…TRPS I is caused by a variety of mutations in the TRPS1 gene, including a gene deletion [ 45 ]. A recent study described a novel genetic variant in the TRPS1 gene that causes syndromic brachydactyly with defects in skeletal formation and growth plate development [ 46 ]. In addition, GWAS studies have found an association of SNPs in the TRPS1 gene with femoral neck bone mineral density [ 47 ] and estimated heel bone mineral density, indicating the importance of the gene in bone remodelling [ 48 ].…”