Fetal Gene Test Uncovers BICD2 Mutation Behind Congenital Knee Dislocation

In a case that illustrates how modern genomics is reshaping prenatal medicine, researchers in China have reported the prenatal diagnosis of congenital dislocation of the knee (CDK) caused by a spontaneous mutation in the BICD2 gene. The report, published in Frontiers in Genetics by a team at Shandong Medical and Pharmaceutical University and the Affiliated Yantai Yuhuangding Hospital of Qingdao University, describes a pregnancy in which routine ultrasound at 25 weeks of gestation revealed a constellation of fetal abnormalities, and whole-exome sequencing subsequently traced them to a single letter change in a gene responsible for shuttling cellular cargo along the highways of the neuron. The case is notable not only for its diagnostic resolution but also for expanding the known prenatal appearance of a rare neuromuscular disorder that has rarely been documented before birth.

Congenital dislocation of the knee is a rare malformation in which the knee joint is malformed or unstable from birth, often presenting as fixed hyperextension of the lower leg. The condition severely affects the quality of life of affected individuals and imposes a heavy burden on families and health systems. Its causes have long remained murky: clinicians have proposed contributions from genetic factors, atrophy of the quadriceps muscle, muscular nutritional imbalance, and mechanical or intrauterine factors. Because the etiology is heterogeneous, distinguishing isolated cases, which often respond well to conservative treatment, from syndromic cases, which carry a far grimmer outlook, is one of the central challenges in prenatal counseling. The new report demonstrates how genomic sequencing can draw that critical line before delivery.

The patient was a 34-year-old woman in her first pregnancy, conceived by artificial insemination, with no underlying disease and no family history of genetic disorders. Early screening had been reassuring: nuchal translucency measured at 12 weeks and 3 days was normal, and second-trimester serum screening at 17 weeks showed only a borderline risk for trisomy 21, at 1 in 790. The turning point came at 25 weeks of gestation, when ultrasound revealed polyhydramnios, an excess of amniotic fluid reflected by an amniotic fluid index of 20.1 centimeters, and a striking absence of observable fetal movements. Fetal akinesia, or lack of movement, is a red flag that frequently signals an underlying neuromuscular disorder.

The ultrasound findings were detailed and, in retrospect, characteristic. In the midsagittal view of the fetal face, the lower lip and chin lacked the normal S-shaped curve, with loss of the so-called reverse-S sign, and the mandibular facial angle measured 43 degrees, below the 50-degree diagnostic threshold for micrognathia, an abnormally small jaw. The limbs were fixed in abnormal postures: the upper arms were flexed across the chest with clenched fists, while the lower legs were crossed with both knees hyperextended. This combination of joint contractures, fixed limb positions, small jaw, and reduced movement pointed away from an isolated skeletal problem and toward a generalized neuromuscular process, prompting the team to recommend invasive genetic testing.

After genetic counseling, the researchers performed whole-exome sequencing on fetal cord blood. The analysis identified a heterozygous missense variant in the BICD2 gene, denoted c.1613A>G, which changes amino acid 538 from tyrosine to cysteine (p.Tyr538Cys). Critically, the variant was absent in both parents, indicating that it had arisen de novo in the fetus. Under the classification criteria of the American College of Medical Genetics and Genomics, the variant was graded as likely pathogenic on the basis of two pieces of evidence: PS2, reflecting de novo occurrence in a patient with the disease phenotype, and PM2, reflecting its absence from population databases. The variant sits in exon 5 of the gene, and testing confirmed the fetus was heterozygous while both parents carried the wild-type sequence.

Understanding why a defect in BICD2 can immobilize a fetus requires a look inside the cell. BICD2 is a cargo adaptor for dynein-1, the molecular motor that hauls freight along microtubule tracks toward the minus ends, generally toward the cell center. As an adaptor, BICD2 couples dynein to diverse cargoes, including RNA molecules, viral particles, and even nuclei, and it is crucial for coordinating motor proteins with their cargoes and regulatory proteins. The protein is built from three major coiled-coil segments with distinct jobs: dynein and its activator dynactin bind to the CC1 segment, the opposing motor kinesin binds to CC2, and known cargoes attach to the C-terminal CC3 segment. In neurons, which can extend over a meter in length, this transport system is nothing short of essential.

Mutations in BICD2 disrupt dynein-mediated transport, impair motor neuron function, and particularly affect the motor neurons of the lower limbs. The gene is the established cause of autosomal dominant spinal muscular atrophy with lower extremity predominance type 2, or SMALED2. The genotype-phenotype correlation for this disorder is relatively well mapped: de novo mutations tend to produce more severe disease, and variants in the CC2 region and the C-terminal cargo-binding region more often cause severe phenotypes. The p.Tyr538Cys change identified in this fetus lies squarely in the CC2 domain, the region that mediates binding of BICD2 to the kinesin motor KIF5B and participates in coordinating bidirectional transport. While the specific functional consequences of this exact variant have not yet been experimentally verified, its location in CC2, the precedent of pathogenic variants in the same region such as p.Arg501Pro, and the severity of the fetal phenotype together fit the established genotype-phenotype pattern of BICD2-related SMALED2.

The diagnosis was confirmed the hard way. Following multidisciplinary discussion, the family opted for termination of the pregnancy at 25 weeks via intra-amniotic instillation of ethacridine lactate. External examination and X-ray after the procedure confirmed the prenatal findings: bilateral flexion contractures of the upper limbs, thumbs held within the palms, the other four fingers clenched, crossed lower limbs, hyperextended knees, and micrognathia. Autopsy findings were consistent with both the prenatal ultrasound and the genetic diagnosis, closing the diagnostic loop and validating the ultrasound criteria that the team used to recognize the disorder in utero.

The report also maps out the differential diagnosis that prenatal specialists must navigate when they encounter fixed knee hyperextension. Congenital knee dislocation may be isolated or syndromic, and sequential scanning along the long axis of the limbs is used to detect the structural anomalies. Among the syndromic mimics are congenital myopathies caused by RYR1, NEB, and ACTA1 variants, with the RYR1- and NEB-related forms particularly important to exclude; prenatally these can show fetal hydrops, large cystic hygromas, and bilateral talipes. Larsen syndrome, caused by FLNB variants and inherited in autosomal dominant or recessive fashion, presents prenatally with multiple joint dislocations or anterior knee dislocation, spinal anomalies, and multisystem abnormalities. BICD2-related SMALED2, by contrast, lacks these features and follows autosomal dominant inheritance. The distinction matters enormously for prognosis: isolated congenital knee dislocation is treated conservatively with casting, orthoses, and gait training, with surgery reserved for refractory cases and the prognosis generally favorable, whereas syndromic cases carry poorer outcomes and often require surgery.

The authors argue that their case carries a practical message for fetal medicine. When ultrasound reveals micrognathia together with lower-limb postural abnormalities, fixed joint positions, reduced fetal movement, and polyhydramnios, BICD2-related SMALED2 should enter the differential diagnosis, and trio whole-exome sequencing, testing the fetus and both parents, should be performed as early as possible. By detailing the ultrasound features of congenital knee dislocation in a molecularly solved case, the report expands the prenatal phenotypic spectrum of BICD2-related disorders and underscores the diagnostic value of exome sequencing when fetal anomalies are detected before birth. For families, an early molecular answer transforms an unexplained set of ultrasound findings into a defined genetic diagnosis, enabling accurate recurrence-risk counseling, since a de novo variant carries a low but nonzero risk of recurrence, and allowing clinical management plans to be built on evidence rather than uncertainty.

Subject of Research: Prenatal genetic diagnosis of congenital knee dislocation caused by a BICD2 gene variant

Article Title: Case Report: Prenatal diagnosis of congenital knee dislocation caused by BICD2 gene variant

Article References: Ge, X., Li, W., Wei, H., & Liu, M. (2026). Case Report: Prenatal diagnosis of congenital knee dislocation caused by BICD2 gene variant. Frontiers in Genetics, 17, Article 1938741. https://doi.org/10.3389/fgene.2026.1938741

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1938741

Keywords: BICD2, congenital knee dislocation, prenatal ultrasound, whole-exome sequencing, SMALED2, micrognathia, dynein, motor neuron disease, fetal akinesia, genetic counseling, ACMG criteria, polyhydramnios