In the evolving landscape of genomic medicine, accurate interpretation of complex genetic data is critical for uncovering the molecular underpinnings of rare and undiagnosed diseases. VarSeq, Golden Helix’s robust and intuitive variant analysis platform, continues to empower researchers and clinicians worldwide in this mission. Recent publications highlight how VarSeq enabled novel insights across diverse cases—from the identification of UGDH as a new dystroglycanopathy gene, to the characterization of dual-hit mechanisms in syndromic intellectual disability, and phenotype reclassification in skeletal dysplasia linked to FLNA variants. These case studies underscore VarSeq’s ability to streamline variant prioritization, enable phenotype-driven analysis, and integrate advanced genomic technologies into clinical workflows.
UDP-glucose dehydrogenase variants cause dystroglycanopathy
UDP-glucose dehydrogenase (UGDH) variants have been associated with hypotonia, developmental delay, and epilepsy. We report the first pathologic evidence of dystroglycanopathy in siblings with UGDH variants. Both presented around 6 months with developmental delay and elevated creatinine kinase. Sibling A developed epilepsy at age 9 years. Muscle biopsy from sibling A showed necrotizing myopathy with reduced matriglycan immunostaining. Western blot revealed α-dystroglycan with abnormally low molecular weight. The siblings shared pathogenic UGDH variants in trans: c.305G>A p.(R102Q) is predicted to disrupt protein structure and function; c.265-6C>G is deleterious to splicing. We propose that UGDH is an additional dystroglycanopathy gene.
A phenotype-driven analysis was performed with PhoRank (VarSeq v2.5.0, Golden Helix Inc, Bozeman, MT) using the search terms “muscular dystrophy,” “seizure,” and “epilepsy.” All variants were submitted to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/).
ACTB Loss-of-Function Variant and AUTS2 Duplication in a Patient with Syndromic Intellectual Disability
Background
The unbiased detection of multiple genetic hits can aid in the identification of molecular etiologies of congenital anomalies and neurodevelopmental disorders, providing deeper insights into their complex genetic underpinnings.
Purpose
To clarify the etiology of a syndromic intellectual disability (ID) case, we performed a reanalysis of exome sequencing data complemented with an optical genome mapping (OGM) assay.
Case Presentation
The patient is a 23-year-old Brazilian male presenting with mild ID associated with speech impairment; behavioral alterations, including self-injury and polyphagia; class III obesity; impaired glomerular function; macrocephaly; facial and foot anomalies; and cryptorchidism.
Genetic Findings
Two genomic variants were detected, each of which was inherited from a parent: a 7q11.22 4.4 Mb duplication encompassing AUTS2, which was inherited from an apparently normal father, and an ACTB likely pathogenic variant (NM_001101.5:c.328dup:p. Leu110Profs*16), inherited from a mildly affected mother. OGM analysis revealed that the duplicated 7q11.21q11.22 segment was in tandem and encompassed the entire AUTS2 sequence; therefore, this gene was not disrupted or inserted into another genomic site.
Conclusion
The presence of these two genomic variants highlights the importance of exploring further genetic factors in patients with more complex phenotypes via molecular testing techniques. In addition, OGM allowed precise localization of the duplication in the patient’s genome and provided insights into its structure, a capability not offered by previous cytogenomic techniques. This is the first publication supporting the simultaneous involvement of both the ACTB loss-of-function (LoF) variant and the AUTS2 duplication in a patient with a complex ID phenotype, suggesting that AUTS2 duplications may have a functional impact.
Trio exome sequencing revealed an ACTB LoF variant inherited from the mother. A – BAM file highlighting a maternally inherited ACTB indel variant. Images extracted from VarSeq software (Golden Helix). B – Predicted effect of the variant on translation: frameshift (signaled by an orange bar) and premature stop codon (indicated in red letters). Nucleotides and amino acids are represented according to the International Union of Pure and Applied Chemistry (IUPAC) nomenclature. The ellipses indicate parts of the sequences that are not represented. WT – “wild type”; Mut – “mutation” (PNG 120 KB)
Frontometaphyseal dysplasia associated with the FLNA p.G1576R variant
This report presents a male patient with frontometaphyseal dysplasia (FMD) caused by a previously reported FLNA variant (NM_001456.4:c.4726G>A (p.Gly1576Arg)) that was maternally inherited. This finding directly contrasts with two previously reported observations of the same variant, which led to the suggestion that it is associated with a clinically distinct phenotype. Unlike these earlier descriptions, which did not report either signs of skeletal dysplasia or the typical facial features of FMD, the individual we report here exhibits, supraorbital hyperostosis, a skeletal dysplasia (small femoral epiphyses and bilateral pes cavus), retentio testis, reduced joint mobility, and a congenital cardiac anomaly (Ebstein anomaly). Furthermore, the previous cases documented uric acid renal stones and increased optic cup-to-disc ratio, both of which are not found in this patient. The previously reported individuals also had prominent keloid scarring, that is commonly encountered in individuals with FMD, but notably our patient exhibited hypertrophic scarring. The phenotype we report here suggests a broader phenotypic spectrum associated with this specific FLNA variant than previously recognized, challenging the view that it represents a separate syndrome of cardiac valvulopathy, keloid scarring, and joint mobility reduction and instead suggests it is likely best included within the spectrum of frontometaphyseal dysplasia.
DNA from the patient was selected using the Twist Comprehensive Exome + Custom Skeletal dysplasia Panel (608 genes) (Twist Bioscience) and sequenced with NovaSeq 6000 (Illumina) with an obtained average coverage of 212X. The subsequent data analysis was performed with a local NGS-core data pipeline and VarSeq (v2.2.5) (Golden Helix). All transcripts were analyzed in coding exons and intron/exon boundaries up to 10 bp. Copy Number Variation (CNV) analysis was performed using Delly and ExomeDepth. Reference genome: hg38. Parental and segregation analysis of the FLNA variant was performed using Sanger sequencing.
As demonstrated by these impactful studies, VarSeq equips genomic professionals with the tools needed to generate clinically relevant insights from complex sequencing data. Whether through its integration of phenotype-driven tools like PhoRank, robust CNV detection, or seamless compatibility with platforms such as exome sequencing and optical genome mapping, VarSeq accelerates diagnostic yield and discovery. In the hands of researchers and clinicians around the globe, VarSeq continues to push the boundaries of rare disease diagnostics—empowering precision medicine, one variant at a time.