March’s Clinical Genomic Insights Across immunodeficiency syndromes, oculocutaneous albinism, and ocular genetics
Each month, we highlight new research from the scientific community that advances our understanding of complex genetic diseases and showcases the tools researchers rely on for precise variant interpretation. Our customer publications in March explored immunodeficiency syndromes, oculocutaneous albinism, and ocular genetics.
Title: Oncostatin M receptor deficiency as a novel candidate genetic cause of autosomal recessive hyper-IgE syndrome
Background: Hyper-immunoglobulin E syndrome (HIES), or Job’s syndrome, is a group of rare inherited immune disorders marked by high IgE levels, eczema, and recurrent skin and lung infections. It is most commonly caused by mutations in the STAT3 gene, but many other genetic defects can produce similar symptoms, making HIES a collection of related conditions rather than a single disease. These mutations disrupt immune signaling pathways, especially those involving Th17 cells, leading to poor defense against infections and increased allergic features.
Objective: This article aims to describe a patient with symptoms consistent with hyper-IgE syndrome, including high IgE levels, eczema, lung infection (aspergillosis), and bone fractures.
Subjects and Methods: Whole-genome sequencing was performed on the patient’s DNA, followed by detailed bioinformatic analysis to identify potentially disease-causing variants. Common variants and those unlikely to affect protein function were filtered out, and candidate variants were evaluated using established clinical and computational criteria.
Results: After analyzing known HIES-associated genes, most identified variants were ruled out based on factors such as high frequency in healthy populations, mismatch with the patient’s clinical features, or inconsistent functional data. Ultimately, the missense variant in the OSMR gene remained the most likely cause of the patient’s condition, as no other plausible genetic explanation was found.
Conclusions: Genetic analysis revealed the patient has a rare homozygous missense mutation in the OSMR gene, suggesting this variant may be the underlying cause of their condition.
How VarSeq Was Used: VarSeq software (version 2.3.0, Golden Helix, Inc.) was used for annotation and filtering of variants. Population frequency (gnomAD Exomes Variant frequencies version 2.0.1, Broad Institute) threshold was set to 1% to exclude common polymorphisms. In addition, sequence ontology was applied so only non-synonymous variants in coding regions of genes or variants, including structural variants predicted to affect translation, were considered. Variants were classified using American College of Medical Genetics and Genomics criteria in part based on annotations, including CADD version 1.5 score, gnomAD frequency, ClinVar submission interpretations, and HGMD Pro version 2022.4 variant classification. The MSC of CADD value with 95% confidence interval was determined by Zhang et al. The cumulative pLOF was calculated by summarizing all allele frequencies (from gnomAD version 4.1.0) from the respective gene. The gene damaging index (GDI-Phred) was determined by Itan et al.
Citation: Sisse Andersen, Kristian Assing, Julie Jensen, Line Dahlerup Rasmussen, Christian B. Laursen, Christoffer D. Dellgren, Daniëla Maria Hinke, Søren E. Degn, Trine H. Mogensen; Oncostatin M receptor deficiency as a novel candidate genetic cause of autosomal recessive hyper-IgE syndrome. J Hum Immun 4 May 2026; 2 (3): e20250119. doi: https://doi.org/10.70962/jhi.20250119
Title: Oculocutaneous albinism variants in 28 consanguineous families and functional classification of a pathogenic deep intron variant in TYR
Background: Oculocutaneous albinism (OCA) is a group of genetically diverse, autosomal recessive disorders characterized by reduced pigmentation of the skin, hair, and eyes, along with vision problems. There are multiple types of OCA caused by different genes, as well as syndromic forms like Hermansky-Pudlak and Chediak-Higashi syndromes, which include additional immune and systemic complications.
Genetic diagnosis is important but remains incomplete in about 30% of cases. One possible explanation is the presence of intronic variants, which can disrupt normal RNA splicing by activating “pseudoexons,” potentially leading to defective or absent proteins.
Objective: The study aimed to examine 28 consanguineous families with oculocutaneous albinism (OCA) in Pakistan, identifying 23 cases of isolated OCA and 5 cases of Hermansky-Pudlak syndrome.
Subjects and Methods: Researchers used targeted next-generation sequencing (NGS) to analyze 20 genes associated with OCA and related conditions, filtering variants based on rarity and predicted impact. In one family, whole genome sequencing and homozygosity mapping were also performed to identify potential disease-causing variants.
Results: In one non-syndromic family, researchers discovered a rare deep intronic variant in the TYR gene that causes abnormal inclusion of a pseudoexon, disrupting normal gene function. This is the first reported disease-causing deep intronic mutation in TYR.
Conclusions: Most of the cases were explained by variants in TYR and OCA2, with additional contributions from other genes, and some variants appear to be founder mutations specific to the Pakistani or South Asian population. Notably, about 18% of families had mutations in genes linked to Hermansky–Pudlak syndrome (HPS), highlighting the importance of including syndromic genes in genetic testing. The researchers also discovered a novel deep intronic variant in TYR that disrupts normal gene splicing, leading to reduced or abnormal protein production, and suggested that splice-modulating therapies could potentially improve gene function.
How VarSeq v2.2.3 Was Used:
NGS gene panel analysis
Targeted Next generation sequencing (NGS) was performed using a SureSelect custom library (Agilent, Santa Clara, California, United States) of a gene panel with 20 genes (AP3B1, BLOC1S3, BLOC1S6, DTNBP1, GPR143, HPS1, HPS3, HPS4, HPS5, HPS6, LRMDA, LYST, MLPH, MYO5A, OCA2, RAB27A, SLC24A5, SLC45A2, TYR, TYRP1) plus a deep intron variant in TYR (rs147546939) known to be associated with a pathogenic haplotype [8]. Three newly identified genes, AP3D1 [9], BLOC1S5 [10] and DCT [11], were not analyzed as they were identified after the design of the NGS panel. Sequencing was performed using Illumina technology (Illumina, San Diego, California, United States) and MiSeq platform (Illumina). For alignment and variant calling SureCall v. 3.5.1.46 (Agilent) were used with default settings. VarSeq v2.2.3 (Golden Helix, Bozeman, Montana, United States) was used for annotation and filtering of variants. Variants were filtered for MAF < 1%, location in coding exons plus 20 bp of intron sequence adjacent to exons. CNV analysis was performed using the CNV caller in VarSeq. Variants were classified using the ACMG/AMP guidelines [12,13,14,15,16], PM2 v 1.0, PS2/PM6 v1.1, PM3 v 1.0, webpage (https://clinicalgenome.org/working-groups/sequence-variant-interpretation/).
Whole genome sequencing and homozygosity mapping
Five members from family ALB2 were analyzed by whole genome sequencing. Blood samples were obtained for ALB2-1, ALB2-2, ALB2-3, ALB2-4, ALB2-6 and ALB2-20 and high molecular DNA was extracted using the Chemagic 360 machine (Perkin Elmer, Waltham, Massachusetts, USA). Whole genome sequencing was performed by BGI Group (Shenzhen, China) using Illumina HiSeq X-ten. A mean coverage of 30 X was provided. Alignment was performed to NCBI hg19 version of the human genome using BWA software. GATK (Broad Institute, MIT Harvard, Cambridge, MA, USA) was used for variant calling (SNV and indels). Data was analyzed using VarSeq software v2.2.3 (Golden Helix, Bozeman, Montana) with settings Variant Allele Fraction (VAF) > 0.2, Minor Allele Frequency (MAF) < 0.005 and location in TYR both coding and noncoding regions. CNV analysis was performed using the CNV caller in VarSeq.
Citation: Farooq, M., Bruun, G.H., Sarusie, M.V.K. et al. Oculocutaneous albinism variants in 28 consanguineous families and functional classification of a pathogenic deep intron variant in TYR. Eur J Hum Genet (2026). https://doi.org/10.1038/s41431-026-02070-5
Title: A digenic contribution of RPGRIP1 and SLC4A4 to juvenile-onset open-angle glaucoma phenotype with concomitant corneal dystrophy
Background: Juvenile open-angle glaucoma is an uncommon form of glaucoma, generally associated with high intraocular pressure and a significant visual field loss.
Objective: This study aimed to determine the genetic cause of a case of high myopia and severely elevated intraocular pressure (50 mmHg) in both eyes, requiring trabeculectomy, despite normal open angles, in a 15-year-old boy from a consanguineous family.
Subjects and Methods: Whole-exome sequencing was performed on the patient and his parents using standard library preparation and high-depth sequencing on an Illumina platform. The data were aligned and analyzed with established bioinformatics tools to identify genetic variants. The study focused on rare, likely pathogenic variants in known juvenile open-angle glaucoma (JOAG) genes, as well as genes linked to corneal stromal dystrophies within the family.
Results: The analysis identified a novel likely pathogenic deletion in the RPGRIP1 gene in both the patient and his father, affecting a highly conserved region of the protein. No significant glaucoma-related regions were found through homozygosity mapping. Additionally, a novel likely pathogenic homozygous variant in the SLC4A4 gene was detected in the patient, with both parents carrying it in a heterozygous state.
Conclusions: The homozygous SLC4A4 mutation is likely the primary cause of glaucoma in the patient, while the RPGRIP1 variant may exacerbate disease severity. Although both genes are linked to glaucoma, the findings from this single-family case suggest a possible digenic contribution to the severe juvenile open-angle glaucoma (JOAG) phenotype, but statistical confirmation is not possible.
How VarSeq 2.0 Was Used: Paired-end whole-exome sequencing (WES) for the parents and the proband was carried out after informed consent. The WES (DNA fragmentation, library preparation, and solution-phase hybrid capture) was performed according to the manufacturer’s instructions (Agilent Technologies). The enriched library was sequenced using the Illumina HiSeq 2500 platform with 150-bp paired-end reads. The read depth was at least 100×. The Burrows–Wheeler Aligner software tool[1] was used to align the sequencing reads with hg19/GRCh37. Bioinformatic analysis was performed using Genome Analysis Toolkit (GATK),[2] and variants were annotated and interpreted using Varseq Ver 2.0 (www.goldenhelix.com/products/VarSeq/index.html). Nonsynonymous missense variants, frameshift variants, and indels in exonic and splice regions that were either likely pathogenic or pathogenic were selected from among known glaucoma genes with a minor allele frequency of <0.001. For genetic evaluation, we focused our search on already known genes associated with JOAG namely, MYOC, CYP1B1, LTBP2, OPTN, ASB10, WDR36, EFEMP1, NTF4, TBK1, FOXC1, and PAX6. We also looked for genes associated with corneal stromal dystrophies in the family.
Citation: Sharma, A., Gupta, V., Gupta, S., Malik, M. A., Vanathi, M., Panigrahi, A., & Kumar, A. (2026). A digenic contribution of RPGRIP1 and SLC4A4 to juvenile-onset open-angle glaucoma phenotype with concomitant corneal dystrophy. Indian Journal of Ophthalmology, 74(2), 300–302. https://doi.org/10.4103/IJO.IJO_2810_24
