A 3.06-Mb interstitial deletion on 12p11.22-12.1 caused brachydactyly type E combined with pectus carinatum.

Background: Brachydactyly, a developmental disorder, refers to shortening of hands/feet due to small or missing metacarpals/metatarsals and/or phalanges. Isolated brachydactyly type E (BDE), characterized by shortened metacarpals and/or metatarsals, consists in a small proportion of patients with Homeobox D13 (HOXD13) or parathyroid-hormone-like hormone (PTHLH) mutations. BDE is often accompanied by other anomalies that are parts of many congenital syndromes. In this study, we investigated a Chinese family presented with BDE combined with pectus carinatum and short stature.

Methods: A four-generation Chinese family was recruited in June 2016. After informed consent was obtained, venous blood was collected, and genomic DNA was extracted by standard procedures. Whole-exome sequencing was performed to screen pathogenic mutation, array comparative genomic hybridization (Array-CGH) analysis was used to analyze copy number variations, and quantitative real-time polymerase chain reaction (PCR), stride over breakpoint PCR (gap-PCR), and Sanger sequencing were performed to confirm the candidate variation.

Results: A 3.06-Mb deletion (chr12:25473650-28536747) was identified and segregated with the phenotype in this family. The deletion region encompasses 23 annotated genes, one of which is PTHLH which has been reported to be causative to the BDE. PTHLH is an important regulator of endochondral bone development. The affected individuals showed bilateral, severe, and generalized brachydactyly with short stature, pectus carinatum, and prematurely fusion of epiphyses. The feature of pectus carinatum has not been described in the PTHLH-related BDE patients previously.

Conclusions: The haploinsufficiency of PTHLH might be responsible for the disease in this family. This study has expanded the knowledge on the phenotypic presentation of PTHLH variation.