Challenges in confirming a diagnosis in skeletal dysplasia
Mar 15, 2021

Given the considerable phenotypic overlap among the over 450 skeletal dysplasias and growth disorders, establishing the precise diagnosis can be a challenge. We looked at over 500 cases from 3 commonly ordered panels in this disease group and recognized key elements to consider that contribute to establishing a molecular diagnosis.

“In recent years, we have come a long way in appreciating the unique characteristics of each skeletal dysplasia. Still, even with today’s knowledge, arriving at a precise clinical diagnosis can require significant medical expertise,” said Alicia Scocchia, certified genetic counselor and clinical liaison at Blueprint Genetics.

Narrowing down the differential diagnosis

According to Scocchia, a collaborative diagnostic approach is often taken to identify the underlying cause of an individual’s skeletal dysplasia, including radiographic and clinical assessment, as well as molecular analysis. This can involve the expertise of many clinicians and technical specialists.

“Clinicians often consult colleagues with special training and experience in interpreting imaging studies for individuals with suspected skeletal dysplasia. Without access to these specialists, one can find it more challenging to achieve a precise clinical diagnosis, especially prenatally.”

Genetic testing is an efficient tool to help arrive at a precise diagnosis and inform individualized treatment and management decisions. Moreover, detection of the molecular etiology confirms the mode of inheritance in the family, which is essential for informed genetic counseling.

Whether a targeted or broad genetic testing strategy is pursued may depend on the clinical presentation and preference of the individual and family being assessed, as well as the specific experience of the individual’s care team.

“Skeletal dysplasias show both genetic heterogeneity, where variation in 2 or more genes can result in similar clinical presentations, as well as phenotypic heterogeneity, where different variation within 1 gene may cause strikingly different clinical presentations. To arrive at a precise diagnosis, it can sometimes be most efficient to test multiple genes concurrently, as in a panel or exome testing.”

Panel composition and technical expertise matters – the diagnostic contributors

In a cohort of over 500 patient cases studied, reports included ~80 genes where diagnostic variants were reported. A data point that was particularly interesting was that variation in about half of these genes uniquely contributed to the molecular diagnosis of a single patient.

The most common genes where variation resulted in molecular diagnoses included those you might expect, including COL2A1, FGFR3 and COL1A1, but also surprising genes such as RMRP and the difficult-to-sequence SHOX gene.

Interestingly, 5 out of 12 cases with diagnostic copy number variation involved loss of the SHOX gene. A diagnostic finding in exon 12 of the ACAN gene was also notable, since this region is difficult to sequence and thus covered suboptimally in many clinical assays. “This shows the importance of continuous assessment and improvement of technological capabilities, such thoughtful strategies to help resolve variation in regions affected by homology or repetitive sequences. Experience navigating these regions backed by high-quality data can be an immense asset,” Scocchia said.

Hurdles for diagnostic findings in a genetic test: “Worth focusing on copy number variants”

Diagnostic copy number variations have been identified in patients with skeletal dysplasias. Making sure the genetic test is able to accurately detect even the smallest CNV events is crucial. In this cohort, the smallest CNV detected was only 241 base pairs.

“In our review of over 500 patient reports from panel testing for skeletal dysplasias, we found over 5% of cases to have a diagnostic CNV finding. It is definitely worth focusing on copy number variants; if comprehensive CNV detection is not included, you may miss a molecular diagnosis for a patient and family,” Scocchia said.

Additionally, there are approximately 250 noncoding variants in genes associated with skeletal dysplasias and growth differences that might not be covered by all standard genetic tests.

“As our understanding of the diagnostic significance of noncoding variants grows, continuing to target noncoding regions of interest maximizes the chance at a molecular diagnosis. A full list of the noncoding variants targeted as part of any panel Blueprint Genetics offers can be found by visiting the panel page on our website.”


In short: Common clinical features and considerations

  • Skeletal dysplasias are characterized by differences in growth patterns due to bone development and maintenance
  • Joint pain or joint mobility limitations are common symptoms in individuals with a skeletal dysplasias
  • Additional clinical features can vary, including congenital heart defects, ocular issues, hearing loss with possible speech difficulties, and sometimes immune deficiency
  • Although each condition is individually rare — collectively the birth incident can be as common as 1 in 5000 individuals

Last modified: March 16, 2021