Expanding the Genomic Spectrum of NHLRC2-Associated FINCA Disease: Integrated Bioinformatic Characterization of a Novel Deep Intronic Variant Predicted to Activate a Pseudoexon
Aug 2026· International Journal of Molecular Sciences· 0 citations· 26 references
TL;DR
A male infant with a severe FINCA-like phenotype is reported, including early-onset hemolytic anemia, pulmonary involvement, neurodevelopmental impairment, growth failure, recurrent infections, and fatal progression at 8.5 months.
Abstract
NHLRC2-associated FINCA disease is an ultra-rare autosomal recessive multisystem disorder caused by biallelic pathogenic variants in NHLRC2. Its mutational spectrum and genotype–phenotype correlations remain incompletely defined, and the contribution of non-coding variants is poorly understood. Here, we report a male infant with a severe FINCA-like phenotype, including early-onset hemolytic anemia, pulmonary involvement, neurodevelopmental impairment, growth failure, recurrent infections, and fatal progression at 8.5 months. Whole-genome sequencing identified a compound heterozygous NHLRC2 genotype comprising the previously reported pathogenic missense variant c.442G>T (p.Asp148Tyr) and a novel deep intronic variant, c.331+6863A>G. Segregation analysis confirmed inheritance from different parents. Integrated genomic and splicing analysis predicted that c.331+6863A>G creates a strong cryptic donor splice site and supports pseudoexon inclusion. Reconstruction of the predicted aberrant transcript indicated premature termination and potential susceptibility to nonsense-mediated mRNA decay. To our knowledge, this is the first reported deep intronic NHLRC2 variant predicted to activate pseudoexon inclusion. Although experimental validation was unavailable, convergent clinical, segregation, population, and computational evidence supports c.331+6863A>G as the most plausible second disease-associated allele. This case expands the genomic spectrum of NHLRC2-associated FINCA disease and highlights the diagnostic value of phenotype-driven whole-genome sequencing.
A Chinese patient presenting with classic hallmarks of MGORS7 alongside atypical clinical features, including hearing and visual impairments is reported, suggesting that growth hormone therapy may be beneficial for growth retardation in patients with MGORS7.
Ying Zhao, Yiyang Fu, Shuying Zhang et al.· Frontiers in Genetics· 0 citations
Hemophagocytic lymphohistiocytosis (HLH) is a severe immunological disorder characterized by dysregulated immune activation. Pathogenic variants in HLH-causative genes serve as diagnostic criteria and guide treatment decisions. However, known genes do not fully explain the molecular basis of many cases, and the polygenic contribution to HLH susceptibility remains poorly characterized. Here, we retrospectively analyzed whole-exome sequencing data from 1241 patients with clinically diagnosed or suspected HLH to characterize the HLH genetic landscape. Rare variant association analysis identified two candidate susceptibility genes,
IKBKG
and
DDX3X
. Functional experiments showed that
IKBKG
knockdown impaired NK cell cytotoxicity and degranulation, supporting a contributory role of
IKBKG
in HLH-related immune dysfunction. Exploratory common variant analysis identified potential susceptibility loci, and an integrated model incorporating rare variant burden and polygenic risk score achieved an AUC of 0.71 in this cohort. These findings expand understanding of HLH genetic architecture and support contributions from both rare and common variants.
Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by inactivating germline variants in DNA mismatch repair genes. Here, we describe a woman who developed colorectal, gastric, and endometrial cancers and was found to have a rare missense variant, MLH1:c.545G > T/p.Arg182Met. The variant, which was located at the last nucleotide of MLH1exon 6, was initially reported by a clinical testing laboratory as being a variant of uncertain significance. In silico analyses predicted that it would cause splicing aberration, and reverse-transcription polymerase chain reaction analysis of total RNA from the patient's peripheral blood cells identified an aberrant MLH1 transcript that skipped the entire exon 6 and caused generation of a premature stop codon (p.Glu153Phefs*8). In accordance with the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines, we reclassified the variant as likely pathogenic. Further additional analysis enabled carrier diagnosis in the patient's relatives. Genetics summary Disorder: Lynch syndrome Ethnicity of the patient: Japanese Gene: MLH1 (19 exons) GenBank accession number: NM_000249.4 Chromosomal assignment: 3p21.3 Type of DNA variant: a germline splice aberration variant Mutation: c.545G > T in exon 6 of MLH1 Methods of mutation detection: PCR-sequencing, RT-PCR.
Ayumi Abe, H. Eguchi, Kimio Matsumura et al.· Japanese Journal of Clinical...· 0 citations
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both upper and lower motor neurons, disturbing communication between the brain and muscles. So far, few reports have been published for the SPG11-associated ALS, and this is the first documented case from Pakistan. We report a rare subtype of ALS with an autosomal recessive mode of inheritance with juvenile onset before 25 years of age in the five affected individuals from two unrelated families. Whole-exome sequencing was performed to identify disease-causing variants, and selected variants were further prioritized based on predicted pathogenicity and similarity to clinical phenotypes. Two homozygous variants within the SPG11 gene were identified as pathogenic according to the ACMG and ClinGen Sequence Variant Interpretation (SVI) Working Group recommendations: a novel truncation (NM_025137.4:c.6738dup, p.Glu2247Ter) variant as validated by Sanger sequencing and a recurrent nonsense (NM_025137.4: c.782C>A, p.Ser261Ter) variant (rs765477482) previously reported in a family affected with autosomal recessive hereditary spastic paraplegia (ARHSP). In silico prediction tools further confirmed their pathogenicity. Five patients with juvenile-onset ALS born to consanguineous parents were found to have homozygous SPG11 gene variants. Our findings describe the overlapping phenotypes ofSPG11-related autosomal recessive juvenile ALS and ARHSP, suggesting that these disorders show a clear overlapping phenotype with common genetic defects. In clinical practice, it is challenging to distinguish between these two disorders. Additional Mendelian cases should be included to clarify further and investigate whether these represent two diverse diseases caused by variants in a single gene.
Riaz Ahmad, Muhammad Naeem, H. Houlden· Molecular Biology Reports· 0 citations
Background Autosomal dominant polycystic kidney disease (ADPKD) is most commonly caused by pathogenic variants in PKD1. Here, we reported the functional characterization of an intronic PKD1 variant identified in an ADPKD-affected family and its subsequent application in preimplantation genetic testing for monogenic disorders (PGT-M). Case presentation A three-generation ADPKD family was enrolled. Whole-exome sequencing revealed a heterozygous PKD1 c.7489 + 5G>A variant, which co-segregated with the disease and was initially classified as a variant of uncertain significance. A minigene assay demonstrated that the variant induced skipping of exon 18, leading to a frameshift (p.Arg2404Valfs*123), supporting its reclassification as pathogenic. The couple underwent PGT-M using trophectoderm biopsy, haplotype linkage analysis, and direct mutation detection. An unaffected pregnancy was achieved, and subsequent prenatal diagnosis confirmed the absence of the variant and a normal chromosomal karyotype. Conclusion We validated a pathogenic splicing variant in PKD1 and successfully applied PGT-M to prevent disease transmission, resulting in an unaffected pregnancy.
Qiong Pan, Yuefang Liu, Xueping Sun et al.· Frontiers in Genetics· 0 citations
The findings suggest that PPP1R12A-related disorders may exhibit a broader phenotypic variability than previously recognized and it is proposed that HL and inner ear malformations may represent novel features associated with this clinical spectrum.
G. Pianigiani, Lara Emily Rosso, Anna Morgan et al.· Genes· 0 citations
