Aug 2026· Journal of Assisted Reproduction and Genetics· 0 citations· 28 references
Medicine
TL;DR
Biallelic pathogenic PATL2 variants constitute a major monogenic driver of refractory GV-predominant OOMD and complete recurrent ART failure and substantially expands the global spectrum of disease-causing PATL2 variants.
Objective This study aims to explore the clinical characteristics, genetic etiology, and individualized treatment strategies of patients with PCOS complicated by oocyte maturation disorders caused by novel compound heterozygous variants of the PATL2 gene, and to expand the mutation and phenotypic spectrum of the PATL2 gene. Methods Clinical data and two cycles of controlled ovarian hyperstimulation (COH) were collected from a 34-year-old patient with primary infertility and PMOS. Genetic analysis was performed using whole-exome sequencing (WES), and variant pathogenicity was predicted by bioinformatics tools. An individualized COH protocol was designed and implemented based on the genetic diagnosis. Results The patient had 8 years of primary infertility. In the first cycle, 10 oocytes were retrieved after COH with an antagonist protocol, all arrested at the germinal vesicle (GV) stage. WES revealed compound heterozygous variants in the PATL2 gene (OMIM: 617743): NM_001145112.1: c.1225-2A > G (splice-site variant) and c.1382 T > C (p.Leu461Pro, missense variant), consistent with autosomal recessive inheritance. Both variants were predicted to be deleterious, and c.1382 T > C was a novel unreported variant. In the second cycle, a long follicular protocol, delayed trigger, segmented oocyte retrieval, and indomethacin for spontaneous ovulation prevention were applied. A total of 24 oocytes were retrieved; however, all remained arrested at the GV stage after in vitro culture, and no mature oocytes were obtained. Conclusion Compound heterozygous variants c.1225-2A > G and c.1382 T > C in PATL2 are the core genetic cause of GV-stage oocyte arrest in this patient. GV arrest caused by PATL2 defects cannot be overcome by conventional or optimized IVF protocols even with individualized COH. WES provides critical evidence for etiological clarification, avoidance of ineffective treatment, and genetic counseling. Donor-oocyte IVF remains the ultimate effective strategy for pregnancy in such patients.
Xiaoxia Song, Lei Yan, Yiwen Zhang et al.· Frontiers in Medicine· 0 citations
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.
A. Rozhkova, Anton Esibov, A. Borkovskaia et al.· International Journal of Mol...· 0 citations
This study identifies novel loss-of-function RSPH4A variants causing PCD through distinct molecular mechanisms, expanding the mutational spectrum of radial spoke head protein-related ciliopathies.
Yuting Lu, Hui-Yan Tang, Kai Chen et al.· Frontiers in Genetics· 0 citations
Background Muscular dystrophies (MDs) are a genetically heterogeneous group of disorders, posing significant diagnostic challenges, especially in populations with high consanguinity. Despite advances in genetic testing, a substantial proportion of patients remain undiagnosed. Whole‐exome sequencing (WES) has emerged as a powerful tool for identifying causal variants in such unresolved cases. To identify the genetic basis of nondystrophinopathic MDs in Iranian families with inconclusive prior genetic testing and to evaluate the diagnostic yield and mutational spectrum in this population. Methods We performed WES on one affected individual from each of 10 unrelated Iranian families with clinically diagnosed MD. Candidate variants were prioritized based on in silico prediction tools (SIFT, PolyPhen‐2, CADD, SpliceAI), population frequency databases (gnomAD, 1000 Genomes, EVS), and ACMG/AMP guidelines. Findings were validated by Sanger sequencing, MLPA, and STR haplotype analysis. Segregation analysis was performed in available family members. Results WES led to a diagnostic yield of 69.2% (9/13 variants in 10 families) after segregation analysis and ACMG‐based reclassification. We identified 13 candidate variants in 10 known MD‐associated genes, including DYSF, SGCA, TK2, MAP3K20, LMNA, COL6A1, COL6A2, ITGA7, MICU1, and SGCB. Among these, seven variants (54%) were novel. The majority of cases (84.6%) followed an autosomal recessive pattern, consistent with high parental consanguinity (70%). Notably, a de novo splice‐site variant in COL6A2 (c.1053+1G>T) was identified in a sporadic case, confirming an autosomal dominant inheritance. Challenges in variant interpretation were observed in families with variants in tightly linked genes (COL6A1 and COL6A2), highlighting the role of linkage disequilibrium in founder populations. Conclusion WES is a highly effective diagnostic strategy for genetically heterogeneous MDs, particularly in consanguineous populations. Our study expands the mutational spectrum of MDs in Iran and provides critical data for genetic counseling, prenatal diagnosis, and future therapeutic development. The high rate of novel variants underscores the importance of population‐specific genomic studies.
Nasibeh Soltani, Zahra Shahbazi, M. Fallah et al.· Human Mutation· 0 citations
Tumors exhibiting mismatch repair deficiency without detectable germline mutations via standard multigene panel testing are often classified as Lynch‐like syndrome. In the present report, we describe the case of a 47‐year‐old man presenting with synchronous axillary sebaceous carcinoma and colonic medullary carcinoma. Although initial germline multigene panel testing failed to identify pathogenic variants, a high degree of pathological suspicion for Muir–Torre syndrome remained. Immunohistochemistry revealed a concordant loss of MSH2 and MSH6 expression in both the extraocular sebaceous carcinoma and the colonic medullary carcinoma. This identical protein‐loss pattern detected across anatomically distinct tumors served as decisive pathological evidence of an underlying germline defect rather than independent biallelic somatic mutations. Consequently, whole‐genome sequencing was performed to resolve the discrepancy between the pathological findings and multigene panel testing results, successfully identifying a germline intronic MSH2 variant (NM_000251.3:c.2459‐12A>G). Subsequent RNA analysis confirmed aberrant splicing with an 11‐bp insertion. In conclusion, the present case illustrates that concordant mismatch repair protein loss across multiple tumors provides compelling morphological evidence to guide pathologists in reconsidering negative panel results and pursuing comprehensive genomic investigation to identify pathogenic intronic variants.
Keisuke Noda, H. Kurohama, Katsuya Matsuda et al.· Pathology international (Pri...· 0 citations
OBJECTIVES
Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is a rare disorder caused by biallelic mutations in ACP5. This study systematically evaluates genetic landscape, clinical features, treatment, and transcriptomics in SPENCDI.
METHODS
Whole-exome sequencing was performed for genetic diagnosis of patients from multiple centers, and tartrate-resistant acid phosphatase (TRAP) activity was measured for novel variants. Previously reported cases were integrated with the current cohort for analysis of genotypes, clinical characteristics, laboratory findings, and treatment responses. Bulk and single-cell RNA sequencing investigated immune signaling alterations.
RESULTS
We identified 17 patients with ACP5 deficiency from Egypt and China, discovering five novel pathogenic variants (A260D, L257P, G32D, K190Nfs*22, and T305Nfs*12). Three novel missense variants were detected with loss of TRAP activity. Clinical manifestations involve multiple systems, with the skeletal system most frequently involved (32.31%), where skeletal dysplasia (94.32%) and short stature (81.82%) are the predominant features. Patients showed elevated inflammatory activity, with enrichment of the NF-κB, MAPK, and cell death pathways, as well as upregulation of type I interferon genes in monocytes. Enhanced IFN-γ signaling interactions between monocytes and Natural Killer cells were observed. Therapeutically, Prednisolone and Azathioprine were the most common effective drugs, while patients treated with the Janus kinase inhibitors Ruxolitinib or Upadacitinib achieved a partial response.
CONCLUSIONS
This study expanded the genetic and clinical spectrum of ACP5 deficiency. An upregulated interferon signature was revealed, and monocytes were identified as a major cellular source of inflammation. These results provide valuable insights for improving the diagnosis and treatment of SPENCDI.
Shiling Zhong, Shuangyue Ma, Yasmine El Chazli et al.· Arthritis & Rheumatology· 0 citations