Front Genet. 2025 Nov 7;16:1553036. doi: 10.3389/fgene.2025.1553036

PMID: 41282474

Armaan Saith, Noor Ul Ain, Jiapeng Ruan, Maniya Kasaiyan, Dhanpat Jain, Gary Israel, Sameet Mehta, Nigel S Bamford, Shiny Nair, Pramod K Mistry

Highlights: This study investigates the genomic basis of phenotypic heterogeneity in Gaucher disease (GD) by applying whole-exome sequencing (WES) to patients with atypical presentations. Out of a cohort of 275 GD patients, 17 individuals (6.2%) were identified with complex phenotypes not fully explained by GBA1 mutations alone. The study revealed that these patients harbored concurrent genetic disorders, including Familial Mediterranean Fever (FMF), Metachromatic Leukodystrophy (MLD), and hereditary iron overload. This "precision medicine" approach enabled tailored therapeutic interventions, such as the addition of colchicine for FMF or phlebotomy for iron overload, significantly improving patient outcomes.

Background: Gaucher disease is a monogenic lysosomal storage disorder caused by biallelic GBA1 mutations. However, patients with identical genotypes (e.g., homozygous p.Asn409Ser) often exhibit vastly different clinical trajectories. While previous research focused on modifier genes within the GD pathway, this study hypothesizes that "blended phenotypes" arising from distinct, co-occurring genetic diseases contribute significantly to this variability.

Objective and Methods: The objective was to develop a precision medicine framework for GD by integrating deep phenotyping with genomic profiling to identify the root causes of atypical clinical features. A longitudinal cohort of 275 GD patients was screened for "red flags" (e.g., recurrent fever, early-onset malignancy, severe myopathy). A subset of 17 patients displaying these atypical features underwent WES. Variants were analyzed using ACMG guidelines to identify concurrent molecular diagnoses.

Material and Methods: The study utilized a "phenotype-first" approach. Genomic DNA was analyzed using WES, and GBA1 genotyping was refined using PacBio long-read sequencing to resolve complex alleles. Detailed clinical data, including organ volumes and biomarkers, were collected longitudinally. Variants in candidate genes (e.g., MEFV, HFE, PKD1, ARSA, MSH6) were annotated based on population allele frequencies (specifically Ashkenazi Jewish datasets) and functional predictions (SIFT, PolyPhen).

Results: The study identified multiple molecular diagnoses in all 17 atypical patients. Key findings included:

·     Inflammation: Four GD1 patients with recurrent serositis had concurrent FMF (MEFV variants) and responded to colchicine.

·     Neurology: A child with GD1 and developmental regression had concurrent Metachromatic Leukodystrophy (ARSA variants). Another patient with GD3 and myoclonic epilepsy carried an EFHC1 variant.

·     Oncology: Two siblings with GD1 and early-onset T-ALL were found to have Constitutional Mismatch Repair Deficiency (MSH6 variants).

·     Metabolism: Five patients with persistent hyperferritinemia despite ERT/SRT had variants in HFE or SLC40A1 genes, necessitating phlebotomy.

Keywords: Gaucher disease, Whole-exome sequencing, Dual diagnosis, Precision medicine, Complex phenotypes, Modifier genes.