A Rare Case of Prenatal Short‐Rib Thoracic Dysplasia 11 Subtype With Compound Heterozygous Variants in the DYNC2I2 Gene: Presenting Polydactyly and Shortened Limbs

ABSTRACT

DYNC2I2‐related Short‐Rib Thoracic Dysplasia 11 can present prenatally with prominent limb shortening and polydactyly as the primary ultrasound findings, while classic thoracic abnormalities may be subtle. This case highlights the condition's clinical heterogeneity and underscores the importance of genetic testing for accurate diagnosis and counseling.

1. Introduction

Skeletal dysplasias encompass a diverse group of genetic disorders characterized by abnormalities in bone and cartilage development, leading to significant variations in skeletal morphology and function. These conditions are often associated with a range of clinical manifestations, including limb shortening, polydactyly, and thoracic constriction. According to the 2023 Nosology of Genetic Skeletal Disorders, Short‐Rib Dysplasia (SRD) group (formerly Short‐Rib Polydactyly Syndrome, SRPS) falls under the category of “skeletal disorders caused by abnormalities of cilia or ciliary signaling” (NOS10‐0040) and is associated with 33 different genes [1]. Among the various subtypes of skeletal dysplasia, Short‐Rib Thoracic Dysplasia (SRTD) represents a particularly severe form, typically characterized by short ribs and a narrowed thorax, which often results in life‐threatening respiratory complications in affected neonates. The incidence of SRTD is estimated to be approximately 1 in 100,000 live births, with most cases linked to pathogenic variants in the DYNC2H1 gene, which is responsible for the more common subtypes, SRTD3 [2, 3, 4]. However, a less prevalent variant, associated with the DYNC2I2 (formerly known as WDR34) gene, leads to the rarer subtype known as SRTD11.

The DYNC2I2 gene encodes the WD repeat‐containing protein 34, which is a component of the mammalian dynein motor‐based intraflagellar transport (IFT) machinery. This machinery is critical for the assembly and maintenance of cilia, which are essential organelles for various signaling pathways crucial for normal development and survival (NCBI Reference: NM_052844.3). Pathogenic variants in DYNC2I2 disrupt ciliary function, leading to the constellation of features seen in ciliopathies like SRTD.

The identification of genetic variants associated with skeletal dysplasia has been greatly facilitated by advancements in genomic technologies, such as whole exome sequencing (ES) and copy number variation sequencing (CNV‐seq). These methods enable comprehensive characterization of genetic alterations, allowing for precise diagnosis and informed genetic counseling. The interpretation of these genetic findings follows established guidelines, such as those from the American College of Medical Genetics and Genomics (ACMG), ensuring that variants are classified based on their potential pathogenicity. In cases where clinical features are atypical or not fully aligned with established phenotypic presentations, as seen in certain cases of DYNC2I2‐related SRTD, the complexity of genotype–phenotype correlations becomes evident. The clinical heterogeneity in DYNC2I2‐related SRTD is significant, ranging from lethal neonatal forms with severe thoracic restriction to milder presentations compatible with longer survival, sometimes with additional features like renal or cardiac anomalies [5]. While classic features include a narrow thorax and short ribs, the severity can vary, and some patients may not present with polydactyly. The disease course is often characterized by severe and worsening respiratory complications, such as recurrent pneumonia and lung hypoplasia, which frequently lead to early mortality even in patients who survive the neonatal period [6]. Extraskeletal manifestations like renal or cardiac anomalies appear to be less common than in other SRTD subtypes. Currently, there are more reports detailing postnatal occurrences of short rib and thoracic dysplasia compared to those focused on fetal presentations [5, 7], indicating a significant gap in our understanding of this condition during prenatal development. The quality of life and overall prognosis for individuals with this type of disorder are typically poor, with thoracic dysplasia frequently leading to respiratory abnormalities that may result in mortality. Prenatal intervention represents a promising approach to managing such conditions; however, this necessitates timely identification of the disease during pregnancy. Early detection is crucial for effective prenatal management and for providing families with appropriate options and support.

2. Methods

2.1. Clinical Data Collection and Analysis

Clinical data were collected through a retrospective review of the patient's electronic medical records, including prenatal ultrasound reports, genetic counseling notes, and postnatal examination records. Fetal biometry was compared against established gestational age‐specific reference ranges. The CARE guidelines were followed for the reporting of this case.

2.2. Exome Sequencing and Analysis

Genomic DNA was extracted from 10 mL amniotic fluid and whole blood of both parents, and chromosomal abnormalities were detected using CNV‐seq. For further detection of variants and small indels, exome sequencing (ES) was performed. Exome capture was carried out with Illumina's Nextera Rapid Capture Exome Kit (Illumina Inc., San Diego, CA, USA). Sequence capture, enrichment, and elution were performed according to the manufacturer's instructions without modification. More than 10 gigabases (Gb) of raw data were obtained, resulting in a coverage of at least 100×, with an average coverage of > 99.2% across target regions.

Sequence reads were mapped to the Human genome build (hg19) by using the Burrows‐Wheeler Aligner tool. The hg19 build was used as the reference genome as it was the standard for our established and validated clinical sequencing pipeline at the time of analysis. The duplicate reads were removed using Picard MarkDuplicates. Then, GATK and SAMtools were applied to create a VCF file containing all the sites with potential variants. VCF files were filtered based on two criteria: depth of coverage and Phred score quality (DP > 10‐’QUAL > 25). To assess the potential of detecting copy number variations (CNVs), we utilized a CNV‐detection pipeline based on ExomeDepth software. After calling variants list, the ANNOVAR software tool was used to annotate screened variations and connect the three annotation modes according to the type of gene, region, and filter. The analysis focused on virtual gene panels composed of genes associated with fetal lateral ventricle dilation, unclear septum pellucidum, hydrocephalus, and agenesis of the corpus callosum.

The pathogenicity of the variants identified by ES classified by the guidelines of ACMG [8]. Sanger sequencing was used to confirm the variants identified by trio ES, Primers for the target region of the variants were designed using Primer3 online software (http://primer3.ut.ee/).

2.3. Clinical Data Collection and Analysis

Clinical data were collected through a retrospective review of the patient's electronic medical records, including prenatal ultrasound reports, genetic counseling notes, and postnatal examination records. Fetal biometry was compared against established gestational age‐specific reference ranges. The CARE guidelines were followed for the reporting of this case.

3. Results

3.1. Clinical Evaluation

A 29‐year‐old Chinese G2P1 woman and her 30‐year‐old non‐consanguineous husband presented at 34 weeks + 1 day of gestation for a prenatal ultrasound. The ultrasound findings indicate significant skeletal anomalies, with femur, tibia, fibula, humerus, ulna, and radius lengths all exhibiting reductions of 2–4 standard deviations (SD) from the norm. (Specific measurements will be detailed in Figure 1a–f). Additional findings demonstrate polydactyly (postaxial polydactyly of both feet and the left hand, Figure 1g–i). The preliminary diagnosis is “polydactyly associated with skeletal dysplasia.” Genetic counseling revealed no family history of similar hereditary diseases (Table 1), and the previous pregnancy resulted in a healthy daughter. These measurements and associated features strongly suggest a diagnosis consistent with skeletal dysplasia.

FIGURE 1.

(a–l) Prenatal ultrasound and postnatal findings of the male fetus at 36 weeks of gestation. Ultrasound findings indicate significant skeletal anomalies, including: (a) Femur length of 57 mm (Z = −2.669), (b) Tibia length of 51 mm (Z = −2.367), (c) Fibula length of 47 mm (Z = −3.214), (d) Humerus length of 46 mm (Z = −4.401), (e) Ulna length of 48 mm (Z = −2.642), (f) Radius length of 44 mm (Z = −1.704), (g, h, j) Postaxial polydactyly of both feet, (i, k) Postaxial polydactyly of the left hand, l: Anteroposterior radiograph demonstrating a narrow, bell‐shaped thoracic cage. (m) X‐ray results of induced abortion fetus: Humerus at 47.46 mm (Z = −4.05), radius at 44.33 mm (Z = −1.734), ulna at 49.5 mm (Z = −2.287), femur at 61.33 mm (Z = −1.479), tibia at 51.04 mm (Z = −2.554), and fibula at 43.5 mm (Z = −4.6). Additional radiographic features include short ribs, small iliac bones with downward spikes, and metaphyseal widening. (n) Pedigree showing the father (I‐1) carrying a DYNC2I2: c.82_83insCA variant, the mother (I‐2) carrying a DYNC2I2: C.981 + 1G>A variant, a healthy 5‐year‐old daughter (II‐1) carrying a paternally inherited c.82_83insCA variant, and a fetus carrying both c.82_83insCA and c.981 + 1G>A variants, inherited from the parents, forming a compound heterozygote.

TABLE 1.

Clinical details of the family.

Case	Parental details			Gestation at diagnosis	Phenotypes (HPO terms)	Obstetric history	Family history	Outcome
1	Maternal	Age	29	34 week + 1 day	Polydactyly (HP:0010442) Short fetal humerus length (HP:0011429) Short fetal femur length (HP:0011428) Short tibia (HP:0005736)	G2P1	Non‐contributory	Pregnancy termination
		Ethnicity	Asia
	Paternal	Age	30
		Ethnicity	Asia

3.2. Genetic Finding

CNVseq analysis revealed no copy number variations (CNVs) larger than 100 kb. Subsequently, ES identified two compound heterozygous variants in the DYNC2I2 gene within the fetus, the variant of DYNC2I2 (NM_052844.4):c.82_83insCA inherited from the father and DYNC2I2 (NM_052844.4): c.981+1G>A inherited from the mother. According to ACMG guidelines, both variants are classified as likely pathogenic. Notably, the healthy 5‐year‐old sister carries only the c.82_83insCA variant (Figure 1n, Figure S1, Table 2). This gene has been previously reported in association with short‐rib thoracic dysplasia (SRTD) 11 with or without polydactyly.

TABLE 2.

Genetic findings in the Family.

Procedure (Gest Age)	Direct/culture?	Performed test	Secondary confirmatory test	Gene (name; REFSEQ)	Known disease (OMIM)	Variant	ACMG classify‐cation	Criteria applied	Inheritance & zygosity	Interpret‐ation
34 week + 1 day	Direct	Exome Sequencing	Sanger Sequencing	WDR34 (NM_052844.4)	Short‐rib thoracic dysplasia 11 with or without polydactyly (OMIM:615633)	c.82_83insCA	Likely pathogenic	PVS1 + PM2_Supporting + PP4	Autosomal recessive Heterozygous	Disease causing
						c.981 + 1G>A	Likely pathogenic	PVS1 + PM2_Supporting+PP4	Autosomal recessive Heterozygous

3.3. Pregnancy Outcomes

Following comprehensive genetic counseling regarding the poor prognosis associated with severe SRTD, the parents elected to terminate the pregnancy at 36 weeks of gestation. The cause of death was induced termination. The postnatal examination of the induced fetus revealed the presence of polydactyly, with limb lengths for the humerus, ulna, tibia, and fibula significantly below 2SD (Figure 1j–k,m). These findings are consistent with the prenatal examination results. The fetus was diagnosed with Short‐Rib Thoracic Dysplasia 11 with polydactyly. Postnatal X‐ray confirmed features consistent with SRTD, including short ribs and a narrow, bell‐shaped thorax (Figure 1l,m).

4. Discussion

SRTD is a rare autosomal recessive disorder, with approximately one case occurring in every 100,000 newborns, most commonly caused by variants in the DYNC2H1 gene, leading to the subtype known as SRTD3. The compound heterozygous variants found in this case correspond to DYNC2I2, which is associated with the rarer subtype, SRTD11. Clinical interventions for this specific subtype are notably limited due to the scarcity of reported cases.

Previous literature has consistently documented that DYNC2I2‐related SRTD is characterized by two classic features: short ribs and a narrowed thorax, which are fundamental to the disease's nomenclature [6]. Schmidt's study reported 11 patients with the STR11 subtype caused by DYNC2I2; all 11 patients exhibited symptoms of short ribs, but only 1 patient presented with polydactyly. Seven patients had symptoms of trident acetabulum with spurs, and the outcomes for these patients were generally poor, with most dying within a few months after birth, and some around the age of 8 due to severe respiratory distress and recurrent infections [5]. However, this case presents a significant deviation, as the fetus exhibited pronounced polydactyly and severe limb shortening as the most prominent features on prenatal ultrasound. While the classic thoracic constriction was not initially the leading diagnostic feature, postnatal radiography confirmed a narrow, bell‐shaped thorax characteristic of SRTD. This discrepancy highlights that in some fetal presentations of SRTD11, limb and digit anomalies may be more readily apparent on ultrasound than the thoracic cage abnormalities. A summary of clinical features from previously reported cases and our current case is presented in Table S1.

Typically, such thoracic constriction in SRTD correlates with lethal outcomes in the neonatal period due to respiratory insufficiency arising from greatly restricted thoracic capacity. The absence of this finding as a primary feature on initial ultrasound in the current case underscores the clinical heterogeneity associated with DYNC2I2 variants, illustrating the complexity of prenatal diagnoses. It emphasizes the importance of early detection and genetic counseling for affected families to navigate the potential implications of these rare genetic disorders. Further research is necessary to explore the full range of DYNC2I2‐related phenotypes and refine prenatal diagnostic approaches. Enhanced understanding of the genotype–phenotype correlation will greatly benefit genetic counseling and patient care in future cases.

5. Conclusions

This case report highlights the complexities and clinical heterogeneity associated with DYNC2I2‐related skeletal dysplasia, particularly in the context of prenatal diagnosis. The subtlety of classic thoracic findings such as short ribs and narrowed thorax on initial prenatal ultrasound in the presented fetus underscores the variability in phenotypic expression linked to this condition. Despite the severe skeletal anomalies observed, including pronounced limb shortening and polydactyly, this case emphasizes the need for heightened awareness and comprehensive genetic evaluation during pregnancy. Additionally, this study enhances the understanding of the phenotypic spectrum of STR11 caused by DYNC2I2, particularly regarding prenatal manifestations. Early detection and accurate genetic counseling are crucial for informing families about potential outcomes and management options. Given the rarity of DYNC2I2‐related skeletal dysplasia and the limited clinical interventions available, further research is essential to elucidate the full spectrum of phenotypic presentations and improve prenatal diagnostic strategies. This case not only contributes valuable insights to the existing literature but also reinforces the importance of ongoing studies aimed at enhancing patient care and supporting families facing the challenges of rare genetic disorders.

Author Contributions

Zhihui Wang: conceptualization, funding acquisition, investigation. Heqin Guan: writing – original draft. Ximei Li: conceptualization. Jielan Liao: methodology. Yong Pan: methodology. Xueqin Dong: data curation, methodology. Xutao Hong: project administration, writing – review and editing.

Funding

The work was supported by a grant from the Basic scientific research projects in Wenzhou City (Y2023010).

Ethics Statement

The studies involving human participants were reviewed and approved by the Ethics staff Association of Wenzhou central hospital (serial number: 2023‐022). Written informed consent to participate in this study was obtained from the participants' legal guardians or next of kin. Additionally, written informed consent for the publication of any potentially identifiable images or data included in this article was also obtained from the legal guardians or next of kin of any individuals and minors.

Consent

Written informed consent was obtained from all participants prior to their inclusion in the study.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Figure S1: Sanger sequencing results for these four family members.

Table S1: Comparison of Clinical Features in Patients with DYNC2I2‐Related Short‐Rib Thoracic Dysplasia 11.

Wang Z., Guan H., Li X., et al., “A Rare Case of Prenatal Short‐Rib Thoracic Dysplasia 11 Subtype With Compound Heterozygous Variants in the DYNC2I2 Gene: Presenting Polydactyly and Shortened Limbs,” Clinical Case Reports 14, no. 1 (2026): e71708, 10.1002/ccr3.71708.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.