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.