Severe brachydactyly and short stature resulting from a novel pathogenic TRPS1 variant within the GATA DNA-binding domain

Abstract

Brachydactyly type E, which can be an isolated finding or part of a syndrome in combination with other clinical anomalies, involves metacarpals and metatarsals with or without short phalanges. Herein we report two unrelated Turkish females who presented with brachydactyly type E and vitamin D deficiency in the absence of marked alterations in serum calcium, phosphate, and parathyroid hormone. After excluding disease-causing variants in two candidate genes, PTHLH and PDE4D, we identified different pathogenic variants in TRPS1, the gene mutated in patients with tricho-rhino-phalangeal syndrome (TRPS). In one of the patients, who displayed severe brachydactyly and short stature, we identified a novel heterozygous missense pathogenic variant in exon 6 (c.2783A>G, p.Tyr928Cys), located within the GATA DNA-binding domain. The second patient, who had relatively milder brachydactyly and was of normal height, carried a heterozygous nonsense pathogenic variant in exon 4 (c. 1870C>T, p.Arg624Ter), which has been previously described. Both pathogenic variants segregated in affected family members. The patients additionally showed sparse hair and a bulbous nose, consistent with the clinical features of TRPS. Our findings, in addition to identifying the genetic cause of brachydactyly in two unrelated kindreds, emphasize the role of pathogenic TRPS1 variants in the development of brachydactyly type E and highlight the GATA DNA-binding region of TRPS1 protein with respect to phenotype-genotype correlation.

Keywords: Brachydactyly type E; GATA DNA-binding domain; Skeletal dysplasia; TRPS1; Tricho-rhino-phalangeal syndrome (TRPS).

Figure 1.. Pedigrees of family A and B.

Affected individuals are indicated by filled symbols and probands by arrows. Individuals whose DNA samples were available for the analysis are shown by Arabic numerals. In Family A, I-2 and III-1 were found to have a novel pathogenic missense variant in TRPS1 exon 6; this variant was not present in individuals II-2 and II-3. In Family B, I-1, II-1, and II-2 were found to have a nonsense variant in TRPS1 exon 4.

Figure 2.. Brachydactyly in Family A. A,B (Individual III-1).

Asymmetric short metacarpals of the proband, with cone-shaped epiphyses at middle phalanges (arrows). C,D (Individual III-1). Short metatarsals in both feet, except for the 2^nd metatarsals. E (Individual I-2). Symmetric short metacarpals of the maternal grandmother, with residual angulated deformity of proximal middle phalanges (arrows) related to fusion of prior cone-shaped epiphyses.

Figure 3.. Brachydactyly in Family B. A (Individual II-1).

Short fifth metacarpals and cone-shaped epiphyses at proximal middle phalanges of the proband (arrows). B (Individual II-2). Short third, fourth, and fifth metacarpals of the proband’s sister, with cone-shaped epiphyses at proximal phalanges (arrows).

Figure 4.. Sequence traces showing the disease-causing nucleotide changes in patients compared to controls.

A. Missense variant in exon 6, p.Tyr928Cys in patient 1. B. Nonsense variant in exon 4, p.Arg624* in patient 2.

Figure 5.. Facial features of the probands with TRPS1-associated BDE.

Photographs of individuals III-1 (A,B) from Family A (Patient 1) and II-1 (C) from Family B (Patient 2). Each patient had a bulbous nose, long flat philtrum, and thin upper lip, although the latter two features were more pronounced in Patient 1.

Figure 6.. Protein sequence conservation at the TRPS1 GATA DNA-binding domain and the modeling of the region comprising Try928.

The multiple alignment of the primary amino acid sequence with orthologs (top) indicate the evolutionary conservation; asterisks, cysteine residues predicted to interact with Zn²⁺. The tyrosine residue at position 928 is delineated on both sides. The peptide modeling (bottom) was performed by using SWISS-MODEL with residues 887–945 (template: human GATA-4). The Zn²⁺ ion and the four interacting cysteine residues are highlighted as ball-and-stick figures, as well as the native tyrosine residue at position 928.