DNA strand and ultrasound of fetus, representing genetic diagnostics and prenatal health.

Unlocking Genetic Mysteries: How Targeted Sequencing Can Help Diagnose Rare Skeletal Conditions

Soraya Malik in Health & Wellness December 2025 • 4 min read.

"Discover the role of targeted next-generation sequencing (NGS) in diagnosing short-rib polydactyly syndrome (SRPS) and improving genetic counseling for families at risk."

Short-rib polydactyly syndromes (SRPSs) are a complex group of skeletal dysplasias with an autosomal recessive or digenic recessive inheritance pattern. These conditions are rooted in ciliary dysfunction and are characterized by distinctive features such as shortened ribs, shortened limbs, and polydactyly (the presence of extra digits). Beyond these primary characteristics, SRPS can also involve a range of associated anomalies affecting critical organs like the kidneys, heart, liver, pancreas, and even the genitalia and intestines. Understanding SRPS requires recognizing its diverse manifestations and the underlying genetic causes.

SRPS is further classified into various types, known as short-rib thoracic dysplasias with or without polydactyly, numbered from 1 to 17 (SRTD1~17). Each type is associated with specific gene loci, such as SRTD1 (OMIM 208500) at gene locus 15q13 and SRTD2 (OMIM 611263) at gene locus 3q25.33. These classifications help clinicians and researchers to categorize and study the syndromes more effectively. The genetic complexity means accurate diagnosis often requires advanced molecular techniques.

While previous studies have reported on SRPS cases linked to NEK1 mutations, this article delves into a specific case of SRTD3, which is associated with mutations in the DYNC2H1 gene. By exploring this particular case, we gain insights into the role of targeted next-generation sequencing (NGS) in diagnosing SRTD3 and providing crucial information for genetic counseling.

What is the Role of Targeted NGS in Diagnosing SRPS/SRTD3?

DNA strand and ultrasound of fetus, representing genetic diagnostics and prenatal health.

In a recent case, a 29-year-old woman, pregnant for the first time, was referred for genetic counseling at 15 weeks of gestation. Ultrasound scans had revealed several abnormalities in the fetus, including shortened limbs, a narrow chest, and bilateral polydactyly affecting both the hands and feet. These findings collectively pointed towards a diagnosis of SRPS type III. Given these indicators, a chorionic villus sampling was performed to obtain a sample for further genetic analysis.

To pinpoint the genetic cause, targeted next-generation sequencing (NGS) was employed. This technique involves analyzing a panel of 25 genes known to be associated with skeletal disorders, including:

CEP120
DYNC2H1
DYNC2LI1
EVC
EVC2
FGFR2
FGFR3
HOXD10
IFT122
IFT140
IFT172
IFT52
IFT80
KIAA0586
NEK1
PAPSS2
SLC26A2
SOX9
TCTEX1D2
TCTN3
TTC21B
WDR19
WDR34
WDR35
WDR60

The NGS analysis identified novel mutations in the DYNC2H1 gene. Specifically, the fetus was found to be a compound heterozygote, carrying two different mutations on the DYNC2H1 gene inherited from each parent:

Implications for Genetic Counseling

This case underscores the utility of targeted NGS in the diagnosis of fetal skeletal dysplasia and SRPS. The information acquired through this advanced genetic testing is invaluable for genetic counseling, enabling healthcare professionals to provide more accurate risk assessments and inform families about potential outcomes and management strategies.

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Everything You Need To Know

What is Short-Rib Polydactyly Syndrome (SRPS), and what are its main characteristics?

Short-Rib Polydactyly Syndromes (SRPSs) are a group of complex skeletal dysplasias characterized by an autosomal recessive or digenic recessive inheritance pattern. They stem from ciliary dysfunction and present with distinctive features. These include shortened ribs and limbs, and polydactyly (extra digits). Additionally, SRPS can involve anomalies in organs like the kidneys, heart, liver, pancreas, genitalia, and intestines. The diverse manifestations and the underlying genetic causes make understanding SRPS essential.

How is Targeted Next-Generation Sequencing (NGS) used to diagnose SRPS, and what specific genes are analyzed?

Targeted Next-Generation Sequencing (NGS) is a crucial tool for diagnosing SRPS by analyzing a panel of genes associated with skeletal disorders. This method was used in a case involving SRTD3, which identified mutations in the DYNC2H1 gene. The panel includes 25 genes such as CEP120, DYNC2H1, EVC, FGFR2, IFT172, NEK1, and SOX9, among others. In the case of SRTD3, NGS helped detect compound heterozygote mutations in the DYNC2H1 gene, inherited from both parents.

Can you explain the difference between SRPS and SRTD and why this classification is important?

SRPS (Short-Rib Polydactyly Syndromes) is a broad category, while SRTD (Short-Rib Thoracic Dysplasias) are specific types within it, often with or without polydactyly. SRTDs are numbered from 1 to 17 (SRTD1~17), each linked to specific gene loci. For example, SRTD1 is associated with the 15q13 gene locus, and SRTD2 with 3q25.33. This classification helps clinicians and researchers categorize and study these syndromes more effectively. This aids in accurate diagnosis through advanced molecular techniques by narrowing down the genetic possibilities.

How does the DYNC2H1 gene relate to SRTD3, and what is the significance of identifying mutations in this gene?

Mutations in the DYNC2H1 gene are associated with SRTD3. The identification of mutations in DYNC2H1 is significant because it provides a specific genetic diagnosis for the condition. In a case involving a 29-year-old pregnant woman, Targeted Next-Generation Sequencing (NGS) revealed the fetus was a compound heterozygote carrying two different mutations on the DYNC2H1 gene. This finding confirmed the diagnosis of SRTD3 and allowed for informed genetic counseling, providing crucial information for families at risk.

What is the role of genetic counseling after a diagnosis of SRPS or SRTD, and how does it benefit families?

Genetic counseling plays a vital role after an SRPS or SRTD diagnosis. The information from advanced genetic testing, such as Targeted Next-Generation Sequencing (NGS), is invaluable. It enables healthcare professionals to provide accurate risk assessments. Counselors inform families about potential outcomes and management strategies. This process helps families understand the condition, plan for the future, and make informed decisions regarding their health and family planning, ensuring they are well-prepared and supported.