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PubMed2026

LINE-1 repeats are a defining feature of the Xce.

During early development, female mammals inactivate one X chromosome to balance their X-linked gene dosage with males. While allelic choice is random in inbred mouse populations, choice can be significantly skewed in interstrain hybrids. The genetic basis of skewing has long been attributed to the mysterious "X chromosome controlling element(s)" (Xce) with different strengths among species, subspecies, and strains. When two X-chromosomes with different Xce strengths are inherited by offspring, the X chromosome with the stronger Xce will have a higher probability of remaining active. Here, we provide evidence that L1Tf repeats-a subfamily of long interspersed nuclear elements 1-plays a role in determining Xce strength. L1Tf elements form a condensed core within the inactive X (Xi) territory. Mouse strains with varying Xce strengths differ in the L1Tf copy number on the X chromosome, with the strength of the Xce allele being inversely related to L1Tf copy number. L1Tf expression mediates the Xce effect. However, in contrast to a prior report, L1Tf RNA does not coat the Xi. Rather, L1Tf promotes condensation of the Xi core. Intriguingly, L1Tfs recruit and sequester YY1 from active genes, accelerating XCI in cis. Thus, L1Tf copy number, expression, and binding of YY1 are key defining features of the Xce. We propose a model in which the Xce influences the choice of Xist alleles by promoting YY1 binding to the nucleation site for the initiation of Xist spreading.

Animals↗

PubMed2015

Perspective on Adeno-Associated Virus Capsid Modification for Duchenne Muscular Dystrophy Gene Therapy.

Duchenne muscular dystrophy (DMD) is a X-linked, progressive childhood myopathy caused by mutations in the dystrophin gene, one of the largest genes in the genome. It is characterized by skeletal and cardiac muscle degeneration and dysfunction leading to cardiac and/or respiratory failure. Adeno-associated virus (AAV) is a highly promising gene therapy vector. AAV gene therapy has resulted in unprecedented clinical success for treating several inherited diseases. However, AAV gene therapy for DMD remains a significant challenge. Hurdles for AAV-mediated DMD gene therapy include the difficulty to package the full-length dystrophin coding sequence in an AAV vector, the necessity for whole-body gene delivery, the immune response to dystrophin and AAV capsid, and the species-specific barriers to translate from animal models to human patients. Capsid engineering aims at improving viral vector properties by rational design and/or forced evolution. In this review, we discuss how to use the state-of-the-art AAV capsid engineering technologies to overcome hurdles in AAV-based DMD gene therapy.

Animals↗

PubMed2026

Mixed Evidence that Dosage Sensitive Genes Drive Global Dosage Compensation in Flour Beetles.

Heteromorphic sex chromosomes create inherent gene dosage differences between males and females because one sex carries a single copy of the X chromosome while the other carries two. Many species have evolved mechanisms that equalize X-linked gene expression between the sexes and, in some cases, restore ancestral autosomal levels, a process known as dosage compensation. Although chromosome-wide compensation is common in male heterogametic (XY) insects, regulatory outcomes vary across taxa and sex chromosome systems, leaving the evolutionary forces shaping sex chromosome regulation unresolved. One hypothesis proposes that the extent to which genes are sensitive to changes in gene dose determines whether complete compensation evolves. We tested predictions of this insensitive sex chromosome hypothesis (ISCH) across five flour beetle species using comparative transcriptomics and genome-wide RNAi-derived measures of gene-by-gene sensitivity. Including an X-autosome fusion in Tribolium confusum allowed direct assessment of expression evolution following a transition from a diploid autosome to a hemizygous Neo-X. Across all five species, we detect complete chromosome-wide dosage compensation and balance between the sexes in somatic tissues, including the Neo-X region. Consistent with ISCH predictions, neither the ancestral Shared-X nor the Neo-X is depleted of genes that are sensitive to RNAi-based expression disruption. However, contrary to expectations, at the level of individual genes, we find little evidence that more sensitive genes exhibit reduced expression divergence. These results suggest that chromosome-wide compensation can be maintained by global regulatory mechanisms that persist through sex chromosome turnover, even when gene-by-gene constraints are weak. Understanding the molecular basis of these mechanisms remains a central challenge in sex chromosome evolution.

Animals↗

PubMed2025

Sex-biased Migration and Demographic History of the Big European Firefly Lampyris noctiluca.

Differential dispersion between the sexes can impact the colonization process and demographic history of a species. Here, we explored the demographic history of the big European firefly, Lampyris noctiluca, which exhibits female neoteny. Distribution of L. noctiluca extends throughout Europe, but nothing is known about its colonization process. To investigate its demographic history, we produced the first Lampyris genome (653 Mb), including an IsoSeq annotation and the identification of the X chromosome. We collected 115 individuals from six populations of L. noctiluca (Finland to Italy) and generated whole-genome re-sequencing data for each individual. We inferred several population expansions and bottlenecks throughout the Pleistocene that correlate with glaciation events. Surprisingly, we uncovered strong population structure and low gene flow. We reject a stepwise, south to north, colonization history scenario and instead uncovered a complex demographic history with a putative eastern European origin. Analyzing the evolutionary history of the mitochondrial genome as well as X-linked and autosomal loci, we found evidence of a maternal colonialization of Germany, putatively from a farther western European population, followed by a male-only migration from south of the Alps (Italy). Overall, investigating the demographic history and colonization patterns of a species should form part of an integrative approach of biodiversity research. Our results provide evidence of sex-biased migration which is important to consider for demographic, biogeographic and species delimitation studies.

Animals↗

PubMed2025

The metabolic costs of meiotic drive.

Selfish genetic elements, such as meiotic drive genes, disrupt Mendel's law of equal segregation by biasing their own transmission, often at a detriment to the rest of the genome. Metabolic costs of the X-linked sex ratio (SR) meiotic drive were investigated in stalk-eyed flies (Teleopsis dalmanni). The experiments demonstrate that individuals with SR have reduced capacity for ATP synthesis. The disruption in mitochondrial function leads to compensation exhibited in increased basal metabolic rate and greater food consumption across a range of diets. The range of metabolic costs of drive was evident in males and females at a similar magnitude. The likely cause lies in the accumulation of deleterious mutations within the series of large inversions on the drive X chromosome, subject to low recombination and weak natural selection. In females, the drive chromosome had a dominant effect, with a single copy causing substantial metabolic compromise. There was little evidence of male-specific metabolic costs, nor evidence of greater effects of drive chromosomes on female metabolism. This suggests that direct metabolic costs from meiotic drive on spermatogenesis and from sexually antagonistic selection are relatively weak. Our results underscore the broad physiological impacts that selfish genetic elements have on host metabolism and fitness.

Animals↗

PubMed2026

Genomic Tracking of Market-Derived Bull Shark Fins Back to Source Population of Origin.

International trade of shark fins remains difficult to monitor because products are rarely labelled to species and are often highly processed, resulting in severely degraded DNA. For several shark species listed under Appendix II of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES), this limits external verification of source populations supplying global trade hubs. Here, we assess whether nuclear genomic approaches can be applied to market-derived bull shark (Carcharhinus leucas) fins to determine their population of origin. We analysed dried fin trimmings collected from retail vendors in Hong Kong SAR, one of the world's largest dried shark fin trade hubs, using a targeted DArTcap single nucleotide polymorphism (SNP) panel, originally developed for population genomic studies of this species. Despite substantial DNA degradation, genomic libraries were successfully obtained for most samples, yielding sufficient SNP data to perform robust provenance and sex assignment. Using a Bayesian mixed-stock analysis, most fin samples were assigned to the Indo-West Pacific (71.4%), with smaller contributions from the western Atlantic (22.6%) and eastern Pacific (3.0%). Genetic sex assignment revealed twice as many males as females, although results indicated a conservative bias towards male assignment due to the limited number of X-linked markers available in degraded samples. Our results demonstrate that genome-wide targeted approaches can be effectively applied to highly processed shark fin products to infer population sources and sex composition. This study provides proof-of-concept for integrating genomics into shark trade monitoring, highlighting its potential to improve traceability, support CITES implementation and inform conservation and fisheries management, particularly for species with well-resolved population structure.

Animals↗

PubMed2026

The Charcot-Marie-Tooth Neuropathy (CMTX3) Complex Structural Variation Causes Differential SOX3 Spatiotemporal Expression.

Charcot-Marie-Tooth (CMT) neuropathy is a clinically and genetically heterogeneous group of diseases characterized by the length-dependent axonal degeneration of peripheral nerves. We previously mapped a rare form of X-linked CMT, CMTX3, to a 5.7-Mb interval on chromosome Xq26.3-q27.1 and excluded the coding region of all known genes in the linkage interval for mutations. Whole genome sequencing subsequently identified a 78-kb region of chromosome 8q24.3 that had been duplicated and inserted into the CMTX3 locus between the genes HAPSTR2 and SOX3. The 78-kb insertion, which contains a partial transcript of ARHGAP39, fully segregated in families with CMTX3 and was absent in neurologically normal controls. To retain the CMTX3 insertion and investigate its consequences in appropriate neuronal tissue, we generated induced pluripotent stem cells (iPSCs) from CMTX3 fibroblasts. Using bulk RNA sequencing of patient-derived spinal motor neurons, ARHGAP39 was deemed nonpathogenic by excluding both the formation of novel fusion transcripts and dosage effects from the partial duplication. Subsequent NanoString expression analyses of candidate genes within the CMTX3 locus, across different stages of neuronal differentiation, identified spatiotemporal dysregulation of SOX3. NanoString showed reduced SOX3 expression in patient iPSCs. RNA sequencing detected SOX3 downregulation in CMTX3 neuroepithelial progenitor cells, which was further confirmed by quantitative proteomics. Given the early onset and relatively rapid progression of CMTX3, these data prioritise SOX3 as a leading candidate gene, consistent with its role as one of the earliest transcription factors expressed in the developing nervous system and a key regulator of neuronal fate.

Humans↗

PubMed2026

First Cornelia de Lange Syndrome Type 4 Caused by the Gonadal Mosaicism of RAD21 Deletion.

BACKGROUND: Cornelia de Lange syndrome (CdLS) currently has seven known causative genes, inherited in an autosomal or X-linked dominant pattern. Clinical features are variable, including dysmorphic facial features, intrauterine and/or postnatal growth retardation, multiple organ system malformations, and neurodevelopmental disorders. Type 4 of CdLS caused by RAD21 gene has a relatively mild phenotype. METHODS: Here, we report a pair of siblings from a Chinese family who both have similar dysmorphic facial features, cleft palate, spina bifida occulta, and limb phenotypes. Whole-genome sequencing (WGS) was performed to analyze the genetic basis of their condition. Gap-PCR was subsequently employed to map the breakpoints in the affected siblings' peripheral blood samples. Additionally, the copy number status of the parents and the father's sperm DNA were evaluated using Gap-PCR and digital PCR (dPCR). RESULTS: Through WGS analysis, a heterozygous deletion was found in the 8q23.3-8q24.11 region of both patients, which includes the full-length RAD21 gene. And we mapped the breakpoint with the peripheral blood samples of the affected siblings using Gap-PCR. The parents' peripheral blood had normal copy number. The father's sperm DNA was negative for the deletion by both Gap-PCR and dPCR, whereas the mother's peripheral blood was also negative, suggesting the deletion is likely due to maternal gonadal mosaicism. CONCLUSIONS: We report a pair of siblings with a complete loss of RAD21, with evidence supporting maternal gonadal mosaicism. This information will be helpful for genetic counseling for Type 4 of CdLS.

Humans↗

PubMed2026

Sex-Specific Diagnostic Inequality in Fabry Disease: Lessons Learned from Analysis of Newborn Screening and Cascade Testing in Tennessee from 2017 to 2024.

INTRODUCTION: Fabry disease (FD) is an X-linked lysosomal storage disease caused by alpha-galactosidase A (aGAL) deficiency. Newborn screening (NBS) programs for FD have been implemented in several US states; however, its effectiveness in identifying affected females remains uncertain. We hypothesized that sex-specific inequality of NBS-based detection of FD results in different diagnostic pathways for males and females with FD. METHODS: We compared diagnostic approaches for males and females with FD using Tennessee NBS results and Vanderbilt Lysosomal Storage Disorders Database (VLSDD). Sex-specific detection differences were assessed using Fisher's exact test (α = 0.05). RESULTS: Tennessee NBS identified 25 males but no females with FD from 2017 to 2024. In VLSDD, among 81 individuals with FD, sex distribution was nearly equal (42 males, 39 females). Among males, 26/42 (62%) were diagnosed via NBS, 7/42 (17%) through known family history, and 9/42 (21%) based on clinical symptoms. All 16 males diagnosed through non-NBS were born before its implementation. In contrast, none of the 39 females were diagnosed through NBS (p value <0.05). Of these, 13/39 (33%) were diagnosed through cascade testing following their sons' detection by NBS, with a median age at diagnosis of 28 years (25th-75th percentile: 24.5-34.0). Of the remaining 26 females, 12/26 (46%) were diagnosed after a family member was diagnosed through clinical symptoms and 14/26 (54%) were diagnosed through clinical symptoms. CONCLUSIONS: NBS effectively identifies affected males but fails to detect females with FD, though it can indirectly facilitate diagnosis of older female relatives.

Humans↗

PubMed2026

Sex-Based Disparities in Fabry Disease Cause Challenges in Newborn Screening.

INTRODUCTION: Fabry disease (FD) is a multi-systemic, X-linked lysosomal storage disorder caused by decreased α-galactosidase activity. Early diagnosis enables timely treatment, but enzyme-based newborn screening (NBS) may not detect affected females. We hypothesized that enzyme-based NBS limitations contribute to sex-based diagnostic disparities in FD and investigated these differences. METHODS: Retrospective cohort analyses used data from the Fabry Registry (FR: 2001-2023) and Tennessee NBS (2017-2024). Sex differences in diagnosis via NBS, biochemical phenotype, symptom onset, and treatment initiation were analyzed using Wilcoxon and chi-square tests. RESULTS: Among 8,657 FR individuals, 73 (67 males, 6 females) were identified via NBS. FR data show that affected females had significantly higher residual α-galactosidase activity than affected males (leukocyte median: 45.9% vs. 3.9%, plasma median: 32.5% vs. 3.9%; p < 0.0001 for both). FR females had delayed symptom onset (18.1 vs. 11.1 years), later diagnosis (35.5 vs. 30.8 years), and lower treatment rates (51.1% vs. 80.8%) compared to males (all %, p < 0.0001). Tennessee NBS detected 25 males but no females. CONCLUSION: Females with FD have delays in symptom onset, diagnosis, and treatment compared to males. Furthermore, higher residual enzyme activity causes current enzyme-based NBS to miss most females. Incorporating sex-specific cutoffs and/or molecular sequencing into NBS could improve early detection and reduce sex-based disparities.

Humans↗

PubMed2025

Splice modulation of COL4A5 reinstates collagen IV assembly in an organoid model of Alport syndrome.

Kidney organoids are an emerging tool for disease modeling, especially genetic diseases. Among these diseases, X-linked Alport syndrome (XLAS) is a hematuric nephropathy affecting the glomerular basement membrane (GBM) secondary to pathogenic variations in the COL4A5 gene encoding the α5 subunit of type IV collagen [α5(IV)]. In patients carrying pathogenic variations affecting splicing, the use of antisense oligonucleotides (ASOs) offers immense therapeutic hope. In this study, we develop a framework combining the use of patient-derived cells and kidney organoids to provide evidence of the therapeutic efficacy of ASOs in XLAS patients. Using multiomics analysis, we describe the development of GBM in WT and mutated human kidney organoids. We show that GBM maturation is a dynamic process, which requires long organoid culture. Then, using semi-automated quantification of α5(IV) at basement membranes in organoids carrying the splicing variants identified in patients, we demonstrate the efficacy of ASO treatment for α5(IV) restoration. These data contribute to our understanding of the development of GBM in kidney organoids and pave the way for a therapeutic screening platform for patients.

Nephritis, Hereditary↗

PubMed2024

Exome sequencing reveals neurodevelopmental genes in simplex consanguineous Iranian families with syndromic autism.

BACKGROUND AND OBJECTIVE: Autosomal recessive genetic disorders pose significant health challenges in regions where consanguineous marriages are prevalent. The utilization of exome sequencing as a frequently employed methodology has enabled a clear delineation of diagnostic efficacy and mode of inheritance within multiplex consanguineous families. However, these aspects remain less elucidated within simplex families. METHODS: In this study involving 12 unrelated simplex Iranian families presenting syndromic autism, we conducted singleton exome sequencing. The identified genetic variants were validated using Sanger sequencing, and for the missense variants in FOXG1 and DMD, 3D protein structure modeling was carried out to substantiate their pathogenicity. To examine the expression patterns of the candidate genes in the fetal brain, adult brain, and muscle, RT-qPCR was employed. RESULTS: In four families, we detected an autosomal dominant gene (FOXG1), an autosomal recessive gene (CHKB), and two X-linked autism genes (IQSEC2 and DMD), indicating diverse inheritance patterns. In the remaining eight families, we were unable to identify any disease-associated genes. As a result, our variant detection rate stood at 33.3% (4/12), surpassing rates reported in similar studies of smaller cohorts. Among the four newly identified coding variants, three are de novo (heterozygous variant p.Trp546Ter in IQSEC2, heterozygous variant p.Ala188Glu in FOXG1, and hemizygous variant p.Leu211Met in DMD), while the homozygous variant p.Glu128Ter in CHKB was inherited from both healthy heterozygous parents. 3D protein structure modeling was carried out for the missense variants in FOXG1 and DMD, which predicted steric hindrance and spatial inhibition, respectively, supporting the pathogenicity of these human mutants. Additionally, the nonsense variant in CHKB is anticipated to influence its dimerization - crucial for choline kinase function - and the nonsense variant in IQSEC2 is predicted to eliminate three functional domains. Consequently, these distinct variants found in four unrelated individuals with autism are likely indicative of loss-of-function mutations. CONCLUSIONS: In our two syndromic autism families, we discovered variants in two muscular dystrophy genes, DMD and CHKB. Given that DMD and CHKB are recognized for their participation in the non-cognitive manifestations of muscular dystrophy, it indicates that some genes transcend the boundary of apparently unrelated clinical categories, thereby establishing a novel connection between ASD and muscular dystrophy. Our findings also shed light on the complex inheritance patterns observed in Iranian consanguineous simplex families and emphasize the connection between autism spectrum disorder and muscular dystrophy. This underscores a likely genetic convergence between neurodevelopmental and neuromuscular disorders.

Humans↗

PubMed2024

Identifying inversions with breakpoints in the Dystrophin gene through long-read sequencing: report of two cases.

BACKGROUND: Duchenne Muscular Dystrophy (DMD) is an X-linked disorder caused by mutations in the DMD gene, with large deletions being the most common type of mutation. Inversions involving the DMD gene are a less frequent cause of the disorder, largely because they often evade detection by standard diagnostic methods such as multiplex ligation probe amplification (MLPA) and whole exome sequencing (WES). CASE PRESENTATION: Our research identified two intrachromosomal inversions involving the dystrophin gene in two unrelated families through Long-read sequencing (LRS). These variants were subsequently confirmed via Sanger sequencing. The first case involved a pericentric inversion extending from DMD intron 47 to Xq27.3. The second case featured a paracentric inversion between DMD intron 42 and Xp21.1, inherited from the mother. In both cases, simple repeat sequences (SRS) were present at the breakpoints of these inversions. CONCLUSIONS: Our findings demonstrate that LRS is an effective tool for detecting atypical mutations. The identification of SRS at the breakpoints in DMD patients enhances our understanding of the mechanisms underlying structural variations, thereby facilitating the exploration of potential treatments.

Humans↗

PubMed2024

Fabry disease in female monozygotic twins with complex intronic haplotype variants: a case report.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disease caused by the impairment of α-galactosidase A. The complex intronic haplotype (CIH) variants, located in promoter and intronic regulatory lesions, has been found in patients with classical forms of Fabry disease. We present a case of Fabry disease in female monozygotic twins exhibiting the CIH mutation and classical manifestations. CASE PRESENTATION: A 61-year-old woman with a history of stroke, carotid artery occlusion, hypertrophic cardiomyopathy, and chronic kidney disease was referred to the nephrology clinic for management of her chronic kidney disease. Her monozygotic twin sister also presented with hypertrophic cardiomyopathy, atrial flutter, carotid stenosis, and proteinuria. Clinical symptoms and a comprehensive family history strongly suggested the presence of Fabry disease. Genetic analysis revealed the presence of 5 variants within a complex intronic haplotype (CIH): c.-10 C > T, c.369 + 990 C > A, c.370 - 81_370-77delCAGCC, c.640-16 A > G, and c.1000-22 C > T. We conducted a review of the patient's previous kidney biopsy findings, which demonstrated the presence of lamellated inclusion bodies in electron microscopy. Remarkably, both the monozygotic twin sister and her son exhibited the same genetic mutation. Enzyme replacement therapy was initiated for the patient. Her kidney function decreased throughout a thorough 2-year follow-up period, while there was a slight decrease in the left ventricular mass index. CONCLUSIONS: This is the first reported case of female monozygotic twins with the CIH variants representing cardiac, cerebrovascular, and renal manifestations suggestive of Fabry disease.

Humans↗

PubMed2022

Current advances in gene therapy of mitochondrial diseases.

Mitochondrial diseases (MD) are a heterogeneous group of multisystem disorders involving metabolic errors. MD are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystem dysfunction with different clinical courses. Most primary MD are autosomal recessive but maternal inheritance (from mtDNA), autosomal dominant, and X-linked inheritance is also known. Mitochondria are unique energy-generating cellular organelles designed to survive and contain their own unique genetic coding material, a circular mtDNA fragment of approximately 16,000 base pairs. The mitochondrial genetic system incorporates closely interacting bi-genomic factors encoded by the nuclear and mitochondrial genomes. Understanding the dynamics of mitochondrial genetics supporting mitochondrial biogenesis is especially important for the development of strategies for the treatment of rare and difficult-to-diagnose diseases. Gene therapy is one of the methods for correcting mitochondrial disorders.

Humans↗

PubMed2026

Duchenne muscular dystrophy: from gene to gene-ius therapies.

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder caused by mutations in the dystrophin gene that result in the absence of functional dystrophin, leading to progressive muscle degeneration, loss of ambulation, respiratory failure, cardiomyopathy, and premature mortality. Despite advances in multidisciplinary supportive care, DMD remains an incurable disease associated with substantial physical, psychosocial, and economic burdens. The monogenic nature of DMD and its well-defined molecular pathogenesis have made it a prime target for the development of precision therapies aimed at restoring dystrophin expression or modifying disease progression. This review provides an overview of the genetic and molecular mechanisms underlying DMD, summarizes its clinical manifestations and natural history, and discusses current standards of care. It further examines recent advances in disease-modifying therapeutic strategies, including exon-skipping antisense oligonucleotides, nonsense mutation readthrough agents, adeno-associated virus (AAV)-mediated micro-dystrophin gene replacement, and emerging genome-editing technologies such as CRISPR/Cas9. The review also highlights the limitations of existing treatments, including mutation specificity, variable efficacy, immune-related challenges, and uncertainties regarding long-term durability and safety. Finally, it considers future directions in therapeutic development, emphasizing the need for combination approaches, improved delivery systems, and next-generation gene-editing platforms to achieve more effective and lasting clinical outcomes. Collectively, these advances represent a paradigm shift in DMD management and offer renewed hope for improving survival and quality of life for affected individuals.

Humans↗

PubMed2026

RNA sequencing resolves a novel noncanonical splice-region variant in PHKA2 causing glycogen storage disease type IX α2: a case report.

BACKGROUND: Glycogen storage disease type IX α2 (GSD IX α2) is an X-linked hepatic glycogenosis caused by pathogenic variants in PHKA2. Noncanonical splice-region variants located outside the invariant GT/AG dinucleotides pose significant interpretive challenges, as in silico predictions alone are often insufficient for definitive classification. CASE DESCRIPTION: We report a 2.9-year-old boy presenting with short stature, hepatomegaly, markedly elevated aminotransferases, fasting hypoglycemia with ketonuria, hypercholesterolemia, coagulation parameter abnormalities (decreased fibrinogen and prolonged thrombin time), and histological evidence of early hepatic fibrosis as demonstrated by Masson's trichrome staining (portal fibrosis and perisinusoidal fibrosis). Whole-exome sequencing (WES) identified a hemizygous, previously unreported PHKA2 variant [NM_000292.3:c.2517+5G>T, genomic location (GRCh38): NC_000023.11: g.18907895G>T], initially classified as a variant of uncertain significance (VUS) under American College of Medical Genetics and Genomics (ACMG) criteria. RNA sequencing of peripheral blood leukocytes demonstrated predominant exon 22 skipping in 94.2% of informative junction reads, predicting a frameshift and premature termination codon [p.(Gly788Profs*74)] with predicted loss of the C-terminal CBL 2 subdomain. Incorporating this transcript-level evidence, the variant was reclassified as pathogenic (PVS1 + PM2_Supporting + PP4). Following dietary management with uncooked cornstarch supplementation, the patient showed progressive biochemical improvement over a 2.2-year follow-up. CONCLUSIONS: This case expands the mutational spectrum of PHKA2 and demonstrates that RNA sequencing of accessible tissues is a practical and diagnostically informative strategy for resolving noncanonical splice-region variants in pediatric hepatic GSD. Early hepatic fibrosis detected by histological examination before age 3 years underscores the importance of longitudinal hepatic surveillance in GSD IX α2.

Glycogen storage disease type IX α2 (GSD IX ↗

PubMed2026

Xp21 contiguous gene deletion syndrome presenting as congenital adrenal hypoplasia: molecular diagnosis and clinical re-evaluation of a pedigree.

OBJECTIVE: To investigate the molecular etiology in a male child clinically suspected of congenital adrenal hyperplasia (CAH) with negative conventional genetic testing, and to elucidate the genetic characteristics of his pedigree. METHODS: Clinical data from the proband and his family members were collected. Molecular diagnostics proceeded sequentially: initial targeted CAH testing (CYP21A2 and POR sequencing/MLPA, plus targeted NR0B1 CNV analysis) was followed by whole-exome sequencing coupled with genome-wide CNV analysis. RESULTS: The proband presented with neonatal cyanosis and hyperpigmentation. Laboratory tests showed markedly elevated ACTH (354.68 pmol/L) and low aldosterone (57.24 pg/mL). Molecular genetic testing identified a hemizygous deletion of approximately 4.44 Mb at Xp21.3-p21.1 (chrX:g.27080000_31520000), encompassing the NR0B1, GK, IL1RAPL1, and DMD genes. CNV-seq confirmed that the mother carried a heterozygous deletion of 4.38 Mb in the same region, while the father and four maternal aunts showed normal genotypes. CONCLUSION: This study ultimately diagnosed the proband with Xp21 contiguous gene deletion syndrome. The adrenal insufficiency resulted from X-linked congenital adrenal hypoplasia (AHC) due to NR0B1 haploinsufficiency, rather than CAH. These findings highlight the considerable clinical overlap between AHC and CAH, indicating that CNV analysis of the Xp21 region should be included in the diagnostic workup for male infants with suspected CAH but negative routine genetic testing. This provides a basis for the precise diagnosis and genetic counseling of such patients.

Humans↗