A 3.06-Mb Interstitial Deletion on Chromosome 12p11.22-12.1 Causes Brachydactyly Type E with Pectus Carinatum

Imagine looking at your hands and seeing fingers that are shorter and stockier than most—not because of an injury, but because the bones in your palms (metacarpals) and finger joints (phalanges) never fully developed. For one four-generation Chinese family, this condition—called brachydactyly—was just one piece of a larger genetic mystery. Their hands and feet were severely shortened, their chests had a distinct forward curve (pectus carinatum), and they were all shorter than average. Now, researchers have uncovered the DNA change responsible: a 3.06-megabase (Mb) deletion on chromosome 12 that disrupts a gene critical for bone growth.

What Is Brachydactyly Type E?

Brachydactyly is a developmental disorder where the bones in the hands and feet are abnormally short or missing. There are five main types, each defined by which bones are affected. Brachydactyly type E (BDE) specifically targets the metacarpals (palm bones) and metatarsals (foot bones), often with short phalanges (finger/toe bones) too. Most BDE cases are part of syndromes (like pseudohypoparathyroidism or acrodysostosis), but a small number are “isolated”—meaning they occur alone. Until now, only two genes were linked to isolated BDE: HOXD13 (which controls limb development) and PTHLH (which regulates bone growth).

A Family with a Unique Combination of Symptoms

The study focused on a Chinese family where nine members across four generations had:

Severe, bilateral BDE: All metacarpals (palm bones) and most phalanges (finger/toe bones) were shortened. X-rays showed “dumbbell-shaped” metacarpals and premature fusion of growth plates (epiphyses), which stop bones from growing.
Pectus carinatum: A chest deformity where the sternum (breastbone) sticks forward, like a bird’s chest.
Short stature: Adult males were under 165 cm (5’5”), adult females under 150 cm (4’11”), and children were well below average height for their age.

Notably, the family had no other issues: no facial abnormalities, intellectual disability, hormone resistance, or dental problems. Blood tests confirmed their calcium, vitamin D, and parathyroid hormone (PTH) levels were normal—ruling out common syndromes linked to BDE.

Solving the Genetic Puzzle

Researchers started with whole-exome sequencing (WES), which reads all the protein-coding parts of DNA. They tested three affected family members but found no mutations in known BDE genes. Next, they used array comparative genomic hybridization (array-CGH)—a tool that detects large chunks of DNA that are missing (deletions) or extra (duplications). This revealed a 3.06-Mb deletion on the short arm of chromosome 12 (12p11.22-12.1).

To confirm the deletion was causing the symptoms, the team used:

Quantitative real-time PCR (Q-PCR): Showed the deletion was present in all affected family members but not in unaffected ones (co-segregation).
Gap-PCR and Sanger sequencing: Precisely mapped the deletion’s breakpoints (chr12:25473650–28536747) and confirmed the junction sequence had a tiny “micro-homology” (the letters “AT”), suggesting the deletion formed via a DNA repair process called non-homologous end joining (NHEJ).

The Key Gene: PTHLH

The 3.06-Mb deletion includes 23 genes, but one stood out: PTHLH (parathyroid hormone-like hormone). This gene makes parathyroid hormone-related protein (PTHrP), a molecule that acts like a conductor for bone development. During growth, PTHrP tells chondrocytes (cartilage cells that become bone) to keep dividing instead of turning into bone cells. This process ensures bones grow long enough before hardening.

When one copy of PTHLH is missing (a condition called haploinsufficiency), there’s not enough PTHrP to regulate chondrocyte growth. The result? Shorter bones in the hands, feet, and—for this family—the sternum.

Previous studies linked PTHLH mutations to BDE and short stature, but this is the first time the gene has been tied to pectus carinatum. Why? Mouse experiments show that Pthlh-deficient mice have narrow, bell-shaped chests—likely because PTHrP is needed for normal sternum development too. The family’s pectus carinatum is a milder version of this mouse phenotype.

Why Symptoms Vary (and Why Testing Matters)

One of the most interesting findings is variable expressivity: even with the same PTHLH deletion, family members had different symptoms. Some had mild hand shortening; others had severe, widespread BDE. This is common in PTHLH-related disorders—genetic modifiers (other genes) or epigenetic factors (how genes are turned on/off) likely play a role.

This variability makes diagnosis hard. For example, the family’s symptoms were initially unclassified because they didn’t fit any known BDE subtype. Genetic testing—especially for CNVs like this deletion—is critical to confirm PTHLH-related BDE and rule out other syndromes.

What This Means for Patients

This study expands our understanding of PTHLH’s role in bone development and adds pectus carinatum to the list of symptoms linked to its haploinsufficiency. For families with similar symptoms, it provides a clear genetic marker for diagnosis. It also highlights the importance of looking beyond single-gene mutations: large DNA deletions (CNVs) are often missed by WES but can be critical to solving rare disease puzzles.

The Researchers Behind the Study

The work was led by Jia Huang, Hong-Yan Liu, Rong-Rong Wang, and colleagues from:

China Medical University (Shenyang): Research Center for Medical Genomics.
Henan Provincial People’s Hospital (Zhengzhou): Institute of Medical Genetics.
Peking Union Medical College (Beijing): McKusick-Zhang Center for Genetic Medicine.

The study was published in the Chinese Medical Journal in 2019.

doi.org/10.1097/CM9.0000000000000327

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