Rare ERBB2 Variants Expand the Genetic Picture of a Multisystem Congenital Disorder

A single child, two never-before-described genetic variants, and a rare developmental disorder that until now had been documented in only two siblings worldwide: a new case report from researchers in Lithuania is drawing attention to just how much remains unknown about the gene ERBB2 and the multisystem congenital disorder associated with it. The study, published as an open-access research article in BMC Pediatrics, describes a seven-year-old boy whose complex presentation at birth and distinctive developmental course broaden both the phenotypic and the genetic spectrum of this emerging condition. For clinicians and geneticists working at the frontier of rare disease diagnosis, the case offers a valuable new reference point for recognizing a disorder so uncommon that most physicians will never encounter it in an entire career.

The patient first came to medical attention at birth with a striking constellation of findings. He presented with hypotonia, meaning diminished muscle tone, along with bilateral talipes equinovarus, the clubfoot deformity in which both feet are twisted inward and downward. His hands showed adducted thumbs, held drawn in toward the palm, and camptodactyly of the index fingers, a permanent flexion contracture of those fingers. Craniofacial dysmorphic features completed the picture of a multisystem congenital syndrome. Taken together, these findings fall within the spectrum of arthrogryposis-like presentations, in which multiple joints are fixed in abnormal positions from before birth, typically reflecting reduced fetal movement or abnormalities of the neuromuscular system during development.

The clinical course that followed was demanding. The boy experienced delayed motor and speech milestones, meaning he reached the stages of sitting, walking, and speaking significantly later than typically developing children. He developed an abnormal gait and suffered from chronic constipation severe enough to require long-term laxative use, a detail that hints at involvement of the autonomic or enteric nervous system. Over the years he underwent multiple orthopedic and ophthalmologic surgeries to address the structural consequences of his condition, and he continues to receive supportive therapies. Notably, his cognitive development remains preserved, a feature that distinguishes his presentation from many other multisystem developmental syndromes in which intellectual disability is a core component.

The genetic explanation emerged through whole exome sequencing, the technique at the heart of modern rare disease diagnosis. Rather than reading the entire three-billion-letter genome, exome sequencing targets the roughly one to two percent of DNA that encodes proteins, where the majority of known disease-causing variants reside. This approach allows laboratories to scan thousands of genes simultaneously in a single test, and it has transformed the diagnosis of congenital disorders by uncovering variants in genes that no one would have suspected from the clinical picture alone. In this patient, sequencing revealed not one but two different variants in ERBB2, one inherited on each of the two copies of the gene, a configuration known as compound heterozygosity.

The two variants are molecularly distinct in ways that matter for interpreting their effects. The first, designated c.1018C>T, converts a cytosine to a thymine at position 1018 of the coding sequence, changing the codon for arginine at position 340 into a premature stop signal, an alteration annotated as p.Arg340Ter. A premature termination codon of this kind typically triggers nonsense-mediated mRNA decay, a cellular quality-control pathway that destroys transcripts containing early stop signals, or else produces a truncated protein lacking essential functional domains. The second variant, c.3412+1_3412+13del, is a deletion that removes the first nucleotide of intron 3412 together with twelve following intronic nucleotides, destroying the canonical splice donor site at that exon-intron boundary. Splice donor mutations of this type generally cause the splicing machinery to skip the preceding exon or retain intronic sequence, either outcome disrupting the reading frame and abolishing functional protein production. The predicted consequence of this second alteration is annotated as uncertain, denoted p.?, reflecting the difficulty of predicting the exact aberrant transcript.

ERBB2 is far better known to the public under another name: HER2, the growth factor receptor famous as a driver and drug target in certain breast cancers. The gene encodes a receptor tyrosine kinase that sits in the cell membrane and partners with the other three members of the ERBB family, EGFR, ERBB3, and ERBB4. When signaling molecules called neuregulins or other ligands engage these receptors, ERBB2 forms dimers with its partners and switches on intracellular cascades, including the MAP kinase and PI3K-AKT pathways, that tell cells to grow, differentiate, and survive. Unlike its relatives, ERBB2 is a preferred dimerization partner with no known soluble ligand of its own, making it a central hub of the signaling network. In developing tissues, particularly the nervous system and the heart, this signaling is essential, which helps explain why germline variants that cripple the gene can produce effects across multiple organ systems.

Before this report, the clinical literature on ERBB2-related congenital disease rested on a remarkably thin foundation: a single family in which two siblings carried a homozygous missense variant, meaning an identical single-letter protein-altering change on both gene copies. That first description established ERBB2 as a gene implicated in rare multisystem developmental disorders, but a phenotype defined by one family is inherently provisional. The new case changes the picture in two ways at once. First, it adds a second, unrelated family, confirming that ERBB2-associated disease is not confined to a single pedigree. Second, it demonstrates that the disorder can arise from a different genetic mechanism, compound heterozygosity for a nonsense variant and a splice-site deletion, rather than a homozygous missense change, and that the resulting phenotype can include features not observed in the original siblings.

The classification of the variants followed established standards. The report references the criteria jointly published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, the framework used worldwide to grade sequence variants as pathogenic, likely pathogenic, uncertain, or benign. Under this system, evidence from population frequency databases such as dbSNP, curated mutation collections such as the Human Gene Mutation Database, computational predictions, and the observed segregation of variants within families all feed into the final classification. The authors’ conclusion that this case represents a possible phenotypic extension of the known disorder is deliberately measured: with only a handful of patients described, distinguishing which features are core to the syndrome and which are variable remains an ongoing challenge that each new case helps to resolve.

The diagnostic journey also illustrates why exome sequencing has become the decisive tool for conditions like this one. A presentation combining clubfoot, contractures, hypotonia, and dysmorphic features could plausibly be attributed to dozens of different genes, and for many years such children accumulated diagnoses of unspecified arthrogryposis or syndromic developmental delay. Sequencing collapses that diagnostic odyssey into a single analysis, and in this case it pinpointed a gene whose connection to congenital disease had been established only once before. The Lithuanian team, based at Vilnius University and Vilnius University Hospital Santaros Klinikos, conducted the work with ethics approval from the Vilnius Regional Biomedical Research Ethics Committee and with written informed consent from the patient’s parents for both participation and publication.

For the emerging field of ERBB2-related medicine, the case carries implications in two directions. In oncology, ERBB2 is one of the most intensively targeted genes in human disease, with engineered antibodies and small-molecule inhibitors transforming outcomes for HER2-positive cancers. In genetics, the same gene is now firmly on the map of recessive congenital disorders, and the new report suggests that the clinical spectrum may be wider than the first family implied, potentially including preserved cognition, chronic gastrointestinal involvement, and a pattern of contractures and deformities requiring serial surgical intervention. Every additional patient described sharpens the genotype-phenotype correlations that clinicians will need to counsel families, interpret future sequencing results, and, eventually, evaluate whether therapies aimed at ERBB2 pathways might one day extend from cancer wards to the care of children with rare developmental disease.

Subject of Research: ERBB2-associated multisystem congenital disorder and the expansion of its phenotypic and genetic spectrum through a novel case report

Article Title: Broadening the phenotypic and genetic spectrum of ERBB2-associated multisystem congenital disorder

Article References: Jakubėnaitė, A., Gurskaitė, G., Morkūnienė, A., & Burnyte, B. (2026). Broadening the phenotypic and genetic spectrum of ERBB2-associated multisystem congenital disorder. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07773-8

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07773-8

Keywords: ERBB2, HER2, whole exome sequencing, congenital anomalies, arthrogryposis, compound heterozygosity, rare disease, craniofacial dysmorphic features, receptor tyrosine kinase, hypotonia, genetics, pediatrics