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PubMed2025

Co-morbid monogenic disorders at chromosome region 1q2: LMNA- and FLG-related disorders in a patient referred for assessment of joint hypermobility.

The phenotypic similarities and genetic heterogeneity occurring in diverse forms of Ehlers Danlos Syndrome (EDS) subtypes and many heritable connective tissue disorders can pose a diagnostic challenge. In the wake of the growing applications of next-generation sequencing technologies including exome and genome sequencing, opportunities for achieving definitive genetic diagnosis are increasingly arising. We present a 46-year-old man with joint laxity, recurrent joint subluxations, pelvic floor dysfunction, and postural orthostatic tachycardia syndrome (POTS), who was referred for EDS assessment. His medical history included morbid obesity requiring gastric bypass surgery, hearing loss, asthma, retinopathy, myopia, atrial septal defect, narcolepsy with cataplexy, polyneuropathy, folliculitis, lichen simplex chronicus, atopic dermatitis, and hypogonadism. His family history was significant for multiple first- and second-degree relatives who died from cardiac diseases including cases of childhood deaths. Physical examination showed joint laxity with Beighton score of 3/9, bilateral pes planus, hearing loss and macrocephaly. Exome sequencing revealed heterozygous variants LMNA c.1262 T > C p.L421P [classified as likely pathogenic], FLG c.2282_2285del p. S761Cfs*36 [classified as pathogenic], and FLG c.1501 C > T p. R501* [classified as pathogenic]. Mitochondria sequencing revealed a variant of uncertain significance (VUS), MT-ND2 m.5047 T > C p.V193A that is present at 9% heteroplasmy in blood. These findings show co-occurrence of pathogenic sequence variants in neighboring genes located in chromosome 1q2 region [LMNA and FLG] in a patient with features of hereditary connective tissue disorders. Our study highlights the capability of exome sequencing in achieving some actionable diagnosis in cases of co-morbid genetic disorders with overlapping and non-specific symptoms.

Humans↗

PubMed2026

Equity in genome sequencing for rare disease diagnosis: a cross-sectional analysis of data from the UK 100,000 Genomes Project.

BACKGROUND: Genome sequencing has improved rare disease diagnosis and is now part of routine clinical care in the National Health Service in England. Automated prioritisation pipelines narrow millions of variants per patient to a small subset for clinical review, a process that relies on allele frequency resources that do not fully represent human genetic diversity. We assessed ancestry-related differences in variant prioritisation and diagnostic outcomes in patients from the UK 100,000 Genomes Project. METHODS: We analysed 29,405 rare disease probands with genome sequencing and linked clinical outcomes data. We used multivariable regression to assess ancestry-related differences in the number of variants prioritised for clinical review, the proportion of prioritised variants that were recorded as diagnostic, and diagnostic yield. We also evaluated the use of ancestry-stratified allele frequency filters derived from an independent, diverse UK cohort (n = 33,724). FINDINGS: Compared with the European ancestry group, the East African group had nearly three times more variants prioritised for clinical review (IRR 2.77, 95% CI 2.33-3.29). Other non-European groups also had significantly higher counts. Diagnostic yield was similar across ancestry groups after adjustment (LRT p = 0.1650). Prioritised variants were less likely to be recorded as diagnostic in East African (OR 0.32, 95% CI 0.22-0.46), West African (0.47, 0.39-0.57), South Asian (0.65, 0.58-0.73), and Middle Eastern (0.68, 0.54-0.86) groups. Applying ancestry-stratified allele-frequency filters removed 3.1% of prioritised variants overall-24.3% in the East African group-without loss of diagnostic sensitivity, including 29.5% of recorded VUS in this group. INTERPRETATION: Differences in the likelihood of prioritised variants being recorded as diagnostic partly reflect limitations of current allele frequency resources, which use broad population groupings that mask within-group diversity. Increased representation of diverse ancestries in reference databases and better estimation of ancestry-appropriate allele frequencies will help reduce inefficiencies and improve equity in variant prioritisation for rare disease diagnosis. FUNDING: The UK Department of Health and Social Care and the EU's Horizon 2020 Research and Innovation Programme.

Humans↗

PubMed2026

Challenges of genomic testing for patients and clinicians in Latin America: Foundations of a qualitative multi-country study.

Genomic medicine is expanding across Latin America (LATAM), yet access to essential ancillary services such as genetic counselling remains limited. 'Latin-SEQ' is a study that provides whole exome sequencing (WES) for neuromuscular diseases across 18 countries, aiming to improve diagnostic rates and generate region-specific genetic insights. However, funding constraints exclude genetic counselling and cascade testing, raising concerns about equitable and harm-free care. This paper reports early findings from 'Latin-SEQ Plus,' a mixed-methods study exploring patient and healthcare practitioner (HCP) perspectives on WES and genetic counselling. Data were generated via surveys with patients and HCPs, and participatory workshops with HCPs across six countries. We found that patients strongly valued genetic testing for diagnostic clarity, improved care, and family planning. HCPs acknowledged the diagnostic benefits of WES but highlighted absence of local genetic counselling services, inconsistent pre and post-test practices, and uncertainty in managing incidental findings and variants of uncertain significance (VUS). Psychological impacts related to WES results are not always addressed, underscoring risks of psychological and emotional harm for patients. Access to WES and genetic counselling is limited in LATAM due to financial hardship and the absence of a clear genetic counselling infrastructure. Our findings also reveal a mismatch between patient expectations and HCPs' capacity to deliver comprehensive genomic care. We argue for urgent investment in genetic counselling infrastructure, HCP training, culturally tailored resources, and policy frameworks to support equitable implementation of genomic medicine in LATAM.

Humans↗

PubMed1998

Improved selection criteria for ordering stat venous ultrasounds from the emergency department.

BACKGROUND: The accuracy and convenience of venous ultrasound (VU) to exclude deep vein thrombosis (DVT) has led to indiscriminate use and low positive yield rates. METHODS: A total of 256 patients were referred from our emergency department (ED) for stat VU during a 2-year period (1995 to 1996). The VUs were interpreted as normal in 198 (77%). Positive findings were discovered in 58 (23%), with DVT accounting for 43 (17%). Retrospective multivariant analysis was used to identify predictive indicators. RESULTS: Unilateral leg swelling/edema identified 36 of 40 (90%) patients with DVT and 8 of 10 (80%) with other thrombotic disorders (saphenous and/or chronic venous thrombosis). A history of leg pain with prior DVT or recent trauma < or =3 days' duration increased DVT duration to 98% (39 of 40). Using these criteria, a 47% charge reduction would have been recognized. CONCLUSIONS: Improving ED screening criteria can safely increase yield rate and reduce charges with minimal loss of VU sensitivity.

Adolescent↗

PubMed1993

Contractile and metabolic properties of longitudinal smooth muscle from rat urinary bladder and the effects of aging.

Longitudinal smooth muscle strips taken from the urinary bladders of Sprague-Dawley rats, aged approximately 6 months and 24 months, were examined under a variety of conditions. Force development in response to electrical field stimulation and to cumulative addition of Ca2+ in the continual presence of 64 mM. KCl was the same in both adult and aged preparations. In response to cumulative additions of carbachol, however, it was observed that there was a shift to the right of the dose-response curve and a decrease in maximal force in the aged muscle strips. The maximal velocity of shortening was significantly lower in muscles from aged animals than in those from young adult animals. The metabolic tension cost during isometric contraction was, however, the same in both groups suggesting that the decline in Vus is largely due to factors not influencing energetic cost. The aged muscles also exhibited a lower basal metabolic rate and a reduced contribution of aerobic glycolysis to total metabolic energy production during both quiescence and stimulation under normoxic conditions than did muscles from young adult animals. They were, however, able to increase their rate of lactate production to the same levels as young adult muscles when stimulated under anoxic conditions.

Adenosine Triphosphate↗

PubMed2026

Analysis of structure and conservation for supporting functional evaluation of PMS2 missense variants.

Germline defects in mismatch repair (MMR) genes are known to significantly increase the risk of developing certain types of cancers, notably colorectal and endometrial cancers. These conditions are characterized under Lynch syndrome. Accurate diagnosis of this predisposition, along with meaningful predictive testing for family members, necessitates the identification of pathogenic variants. However, classifying small coding genetic variants identified in cancer patients is very challenging, specifically in the case of PMS2 variants, since PMS2 pathogenic variants display a lower penetrance and less severe phenotype and therefore a lower tumor burden in affected families. We have assembled clinical data on four PMS2 missense variants of uncertain significance (VUS) identified in 23 patients (p.(Asp286Gly), p.(Asn335Ser), p.(Ile679Thr) and p.(Arg799Trp)). For these variants, functional testing was performed (RNA splicing, protein stability and catalytic activity). Since many protein ortholog sequences and accurate predictive models from AlphaFold2 are available, we also included a systematic analysis of residue conservation and structural role (ConStruct assessment). Overall, our findings indicate that p.(Asp286Gly) and p.(Arg799Trp) behave similarly to wild-type PMS2 and are thus probably neutral. In contrast, p.(Asn335Ser) and p.(Ile679Thr) conferred defects in protein expression or MMR activity. These could be explained by the relevant roles of these amino acids in MLH1-PMS2-N-terminal dimerization (p.Asn335) and C-terminal dimerization (p.Ile679). Our data thus suggest that p.(Asp286Gly) and p.(Arg799Trp) are benign, while the tumor risk in the other two variants remains to be established. Taken together, we suggest roadmaps for the individualized evaluation of difficult uncertain variants by comprising information from all available sources.

Humans↗

PubMed2026

Long-read sequencing reveals a hidden Alu-mediated splice defect in CPLANE1, causing orofaciodigital syndrome type VI.

Orofaciodigital syndrome type VI (OFD VI) is a recessive ciliopathy characterized by excessive polydactyly, molar tooth sign, cleft lip, and developmental delay, caused by pathogenic variants in CPLANE1. Here, we present a patient with OFD VI that remained genetically unexplained after routine genetic testing, including short-read whole genome sequencing (WGS). Using long-read sequencing, we found two biallelic splice-site variants in CPLANE1, c.8633-4_8633-3del, and an Alu element insertion close to an exon-intron boundary. Transcript analysis showed that each variant independently resulted in exon skipping, and quantitative expression studies revealed reduced total CPLANE1 mRNA levels in patient-derived fibroblasts. Based on these findings, we were able to re-classify the c.8633-4_8633-3del variant from a variant of uncertain significance (VUS) to likely pathogenic. The identification of an Alu element insertion missed by short-read WGS highlights the added diagnostic value of long-read sequencing in uncovering cryptic, transposable element-associated pathogenic variants.

Journal Article↗

PubMed2026

Targeted reflex RNA sequencing for enhanced variant classification on exome and genome sequencing improves patient outcomes.

RNA sequencing (RNA-seq) has been utilized to provide functional evidence regarding the impact of splicing variants. This study explores the utility of targeted reflex RNA-seq to inform classification of predicted splicing variants identified through clinical exome sequencing (ES) and genome sequencing (GS). A retrospective analysis was conducted on consecutive ES/GS cases completed at a single center in which targeted reflex RNA-seq was performed following identification of eligible variants. There were 131 cases (4.1%) that had at least one RNA-seq eligible variant reported, with eight of these cases having two unique eligible variants. Of the 139 eligible variants, 125 were classified as variants of uncertain significance (VUS). Sixty-four cases had targeted reflex RNA-seq completed with 27 cases having at least one variant reclassified (42.2%). After reclassification, 23 cases had positive results, and two cases had a likely diagnosis of an autosomal recessive condition. Clinical outcomes data regarding positive RNA-seq cases showed that 71% (10/14) had clinical management changes and 43% (6/14) had treatment changes. Incorporation of targeted reflex RNA-seq analysis into the diagnostic pipeline of rare diseases enhances variant classification and resolves uncertainty regarding predicted splice variants, leading to an estimated 1.6% increase in diagnostic yield of clinical ES/GS.

Journal Article↗

PubMed1998

The standardized psychometric assessment of altered states of consciousness (ASCs) in humans.

The APZ questionnaire was developed in order to explore hypotheses on ASCs. First -- in a series of 11 experiments using different induction methods on N = 393 healthy subjects -- the hypothesis was tested that ASCs have major dimensions in common irrespective of the mode of their induction. In the International Study on Altered States of Consciousness (ISASC) the external validity of the experimental results was assessed. The ISASC was carried out on a total of N = 1133 subjects in six countries. The main results of the experimental studies were corroborated in the field studies. The results can be summarized as follows: the common denominator of ASCs is described by three oblique dimensions, designated as "Oceanic Boundlessness (OSE)", "Dread of Ego Dissolution (AIA)" and "Visionary Restructuralization (VUS)". The reliability and validity of the scales are satisfactory. Tested versions of the APZ scales are available in English (UK, USA), German, Italian and Portuguese. Psychometrically as yet untested versions exist in Dutch, Finnish, French, Greek, Spanish and Russian. The APZ questionnaire has become the international standard for the assessment of ASCs, thus helping to integrate research. A psychometrically improved version exists in German (OAV questionnaire). The BETA questionnaire, which measures the dimensions "Vigilance Reduction (VIR)" and "Auditive Alteration (AVE)" is also available in German. These dimensions are most likely etiology-dependent.

Clinical Trials as Topic↗

PubMed2005

Recruitment, genetic counseling, and BRCA testing for underserved women at a public hospital.

Genetic counseling and testing for heritable susceptibility to breast cancer caused by mutations in BRCA genes are largely unavailable to underserved women in the United States. Starting in 2002 the UCSF Cancer Risk Program offered this service free of charge to poor and medically indigent women at San Francisco General Hospital (SFGH). One recruitment strategy was a single-page questionnaire in four languages administered to women waiting for mammograms at SFGH. This report analyzes our first 3 years of experience with the recruitment questionnaire and compares the patient demographics and BRCA test results at SFGH with a more typical population undergoing genetic counseling and testing at UCSF's Mt. Zion Hospital (MZH). To our knowledge this is the first comprehensive clinical service for hereditary breast cancer in a U.S. public hospital. The ethnic mix of all 350 patients counseled was Caucasian 49% (approximately 20% of Caucasians reported Ashkenazi Jewish ancestry), Latina, 26%; African American, 13%; and Asian/other, 12%. Compared to the MZH population, SFGH patients were more ethnically diverse, less educated and more likely to be unemployed. Of 72 patients tested for BRCA mutations, 51 (71%) were negative, 5 were BRCA1 positive, and 12 were BRCA2 positive. Four (1 Caucasian, 1 Latina, 2 African American) had a total of 13 BRCA variants of unknown significance (VUS). The ratio of BRCA1/BRCA2 positive SFGH patients (5/12) was reversed compared to MZH (119/91). We evaluated 4573 recruitment questionnaires and 280 (6%) were judged to represent a high risk of heritable cancer. After additional screening and referral negotiation, 74 were scheduled for counseling. We judged the recruitment questionnaire to be a feasible, efficient, and reasonably cost-effective way to identify women at high risk of hereditary cancer in a traditionally underserved population. Underserved populations present special challenges for genetic counselors because of large, geographically dispersed families, cultural taboos about cancer diagnoses, and social marginalization. Despite these complexities, the clinical service at SFGH has been well accepted by patients and staff. Our successful venture can serve as a model for other public hospitals contemplating this clinical service.

Adult↗

PubMed2026

Genetic landscape of pediatric seizures in Southeast China: identification of a novel GLI3 frameshift variant through whole-exome sequencing.

BACKGROUND: Pediatric seizure disorders are clinically and genetically heterogeneous. Whole-exome sequencing has improved the detection of rare genetic variants in childhood epilepsy; however, data from pediatric populations in Southeast China remain limited. This study aimed to characterize the genetic landscape of pediatric seizure disorders in Southeast China and to evaluate the clinical diagnostic yield of whole-exome sequencing. MATERIALS AND METHODS: This retrospective observational study included 21 pediatric patients with seizure disorders who were recruited at the Fifth Hospital of Xiamen, Fujian, China, between January 2021 and June 2024. Clinical data were extracted from medical records. Whole-exome sequencing was performed on DNA extracted from peripheral blood. Sequence variants were annotated, filtered, and classified according to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Copy-number variants were evaluated using exome-based algorithms. Descriptive statistics were used because of the limited sample size. RESULTS: WES identified three clinically relevant, likely pathogenic findings in 3 of 21 patients, corresponding to a provisional diagnostic yield of 14.3%. The remaining 62 of 65 variants were of uncertain significance (VUS). The three retained variants included a GLI3 frameshift variant (exon 2: c.90_91insCAGATGTGAGC; p.Glu31Glnfs*3) and two copy-number variants (16p13.12-16p13.11 duplication and Xp22.31 deletion) with established clinical significance. Functional analysis of all 65 variants revealed that ion channel genes and neurodevelopmental genes were the most frequently affected categories. CONCLUSION: Whole-exome sequencing identified clinically relevant genetic findings in a subset of Southeast Chinese children with seizure disorders. The novel GLI3 frameshift variant may suggest an expansion of the GLI3-associated phenotypic spectrum, but further segregation, functional validation, and larger cohort studies are needed. The high proportion of variants of uncertain significance highlights the ongoing challenges of genetic interpretation in pediatric seizure disorders.

GLI3 frameshift variant↗

PubMed2006

Three-class ROC analysis--a decision theoretic approach under the ideal observer framework.

Receiver operating characteristic (ROC) analysis is well established in the evaluation of systems involving binary classification tasks. However, medical tests often require distinguishing among more than two diagnostic alternatives. The goal of this work was to develop an ROC analysis method for three-class classification tasks. Based on decision theory, we developed a method for three-class ROC analysis. In this method, the objects were classified by making the decision that provided the maximal utility relative to the other two. By making assumptions about the magnitudes of the relative utilities of incorrect decisions, we found a decision model that maximized the expected utility of the decisions when using log-likelihood ratios as decision variables. This decision model consists of a two-dimensional decision plane with log likelihood ratios as the axes and a decision structure that separates the plane into three regions. Moving the decision structure over the decision plane, which corresponds to moving the decision threshold in two-class ROC analysis, and computing the true class 1, 2, and 3 fractions defined a three-class ROC surface. We have shown that the resulting three-class ROC surface shares many features with the two-class ROC curve; i.e., using the log likelihood ratios as the decision variables results in maximal expected utility of the decisions, and the optimal operating point for a given diagnostic setting (set of relative utilities and disease prevalences) lies on the surface. The volume under the three-class surface (VUS) serves as a figure-of-merit to evaluate different data acquisition systems or image processing and reconstruction methods when the assumed utility constraints are relevant.

Algorithms↗

PubMed2004

Analysing chronic spinal changes in ankylosing spondylitis: a systematic comparison of conventional x rays with magnetic resonance imaging using established and new scoring systems.

OBJECTIVES: To compare conventional radiography and magnetic resonance imaging (MRI) for detection of chronic changes in the spine of patients with ankylosing spondylitis (AS). METHODS: Assessment of chronic lesions in conventional x rays and T1 weighted MRI turbo spin echo sequences was performed with the established x ray scores BASRI and SASSS, the new Berlin score, and the MRI scoring system ASspiMRI-c All images were read twice and "blindly" by two readers. One vertebral unit (VU) was defined as the region between two virtual lines drawn through the middle of each vertebra. Definite involvement was defined as a score > or =2 in a spinal segment. RESULTS: Thirty nine patients with AS were examined (25 (64%) male, mean age 40.9 years, 33/36 (92%) HLA-B27 positive). The Berlin score correlated with the BASRI (r = 0.73, p = 0.01). The ASspiMRI-c correlated well with the BASRI and the Berlin score (r = 0.66 and r = 0.51, respectively, p = 0.01). The Berlin x ray score showed that 12/35 (34.3%), 13/35 (37.1%), and 12/28 (31.6%) patients had definite involvement of the cervical spine (CS), thoracic spine (TS), and lumbar spine (LS), respectively. The ASspiMRI-c showed that 10/36 (27.8%), 21/36 (58.3%), and 9/35 (25.7%) patients had definite involvement of the CS, TS, and LS, respectively. Syndesmophytes were found in 14.4% of all VUs with 90% agreement between the SASSS and Berlin score. CONCLUSIONS: T1 weighted MRI can detect chronic lesions in AS. The two new scoring systems proved valid in comparison with established scoring systems and based on aspects of the OMERACT filter. The thoracic spine is most commonly affected in AS. This part of the spine is best assessed by MRI.

Adult↗

PubMed2026

Tackling non-canonical splicing in arrhythmogenic cardiomyopathy to reduce the uncertain significance variants burden.

BACKGROUND: Splice-altering variants (SAVs), particularly those outside canonical splice sites, are an underappreciated contributor to inherited cardiovascular diseases. In arrhythmogenic cardiomyopathy (ACM), these variants frequently remain classified as of uncertain significance (VUS) due to limited predictive power and lack of transcript-level evidence, constraining genetic yield and clinical management. Our study aimed to determine the functional impact of SAVs in ACM genes and refine their classification using ACMG/AMP and ClinGen SVI criteria. METHODS: SAVs identified in 200 ACM probands underwent SpliceAI prediction, GTEx cardiac exon-usage annotation, and functional assessment using pSPL3-based minigene assays. Aberrant transcripts were quantified using Percent Splicing Alteration (PSA). Segregation data and ACMG/AMP criteria refined by ClinGen SVI were applied to integrate functional and clinical evidence for classification. RESULTS: Aberrant splicing was confirmed in 9/20 variants (45%), including synonymous, missense, and non-canonical intronic changes. SpliceAI scores correlated strongly with PSA values (R²=0.86). Case-control burden testing revealed significant enrichment of splice-altering variants in DSP, DSG2, DSC2 and FLNC. Integrating predictive algorithms with experimental validation and segregation analysis markedly enhances reclassification of 16/20 variants (80%). CONCLUSION: Splicing defects beyond canonical sites significantly shape ACM genetic landscape. Integrating predictive models with experimental validation clarifies uncertain variants bridging the gap between genomic uncertainty and clinical decision-making.

Humans↗

PubMed2026

Whole-exome sequencing-centered genetic evaluation for early-onset obesity in Chinese children: a retrospective single-center cohort.

BACKGROUND: Genetic causes of early-onset obesity remain undercharacterized in East Asian children. This study evaluated a whole-exome sequencing (WES)-centered diagnostic workflow in Chinese children with obesity onset before 5 years. METHODS: Consecutive children with body mass index above the 95th percentile and obesity onset before 5 years who completed structured inpatient assessment at a single center between February 2022 and December 2023 were retrospectively analyzed. Phenotyping included clinical, biochemical, oral glucose tolerance, cortisol rhythm, and liver assessments. Genetic testing combined WES, mitochondrial DNA analysis, multiplex ligation-dependent probe amplification (MLPA) for obesity-related imprinting loci, WES-based copy-number variant and runs-of-homozygosity analyses, and Sanger validation. Variants were interpreted according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. RESULTS: Among 23 children, clinically relevant genetic findings were identified in 6 (26.1%): melanocortin-4 receptor (MC4R) c.831T>A (p.C277*), maternal uniparental disomy of 15q11-13, and four phenotype-correlated variants of uncertain significance in UCP3, BBS1, NCOA1, and SH2B1. The definitive/likely diagnostic yield, restricted to pathogenic or confirmed imprinting findings, was 8.7% (2/23). Findings involved leptin-MC4R signaling, BBSome function, fatty-acid oxidation, and chromosomal imprinting. Genetically positive children showed numerically higher alanine aminotransferase (ALT) and aspartate aminotransferase (AST), but differences were not statistically significant. BBS1 p.T374S was relatively enriched in East Asian reference data. CONCLUSIONS: A WES-centered integrated workflow detected heterogeneous genetic mechanisms in Chinese children with early-onset obesity, but variant of uncertain significance (VUS)-associated findings should be distinguished from confirmed diagnoses. Orthogonal methylation/MLPA and runs of homozygosity (ROH) analyses were necessary for imprinting diagnosis. Larger multicenter studies and functional validation are needed.

Chinese children↗

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

Novel compound heterozygous POR variants in a neonate with Antley-Bixler syndrome and 46,XY DSD: a case report and literature review.

BACKGROUND: Cytochrome P450 oxidoreductase deficiency (PORD) is an ultra-rare autosomal recessive disorder within the congenital adrenal hyperplasia (CAH) spectrum, characterized by a broad clinical spectrum involving steroidogenesis defects, genital anomalies, and skeletal abnormalities. CASE PRESENTATION: We report a phenotypically female neonate with a 46,XY karyotype whose postnatal diagnostic evaluation was initiated after newborn screening revealed elevated 17-hydroxyprogesterone (17-OHP) concentration. The patient presented with mild hypertelorism, mild nasal hypoplasia, and low-set bilateral ears, along with female external genitalia consistent with disorder of sex development (DSD) and anal atresia. Radiological evaluation revealed femoral bowing and subsequent fracture. The craniofacial and skeletal abnormalities were consistent with the features of Antley-Bixler syndrome (ABS). Endocrine evaluation revealed elevated progesterone, markedly reduced testosterone, and secondary hyperaldosteronism. Genetic analysis identified three novel variants in the POR gene (NM_001395413.1): the patient harbored a paternal c.1187_1195dup (p.Pro396_Glu398dup) variant and two maternally inherited variants in cis, c.1447G>A (p.Gly483Ser) and c.1806 + 4_1806 + 28del. Protein structural modeling predicted that the p.Pro396_Glu398dup and p.Gly483Ser may disrupt the flavin adenine dinucleotide (FAD)-binding domain. RNA sequencing (RNA-seq) confirmed that the intronic variant c.1806 + 4_1806 + 28del caused aberrant splicing, resulting in partial intron retention and predicted impairment of the nicotinamide adenine dinucleotide phosphate (NADPH)-binding domain. According to American College of Medical Genetics and Genomics (ACMG) guidelines and incorporating functional evidence, c.1187_1195dup and c.1806 + 4_1806 + 28del were reclassified as likely pathogenic (LP), whereas c.1447G>A remained a variant of uncertain significance (VUS). CONCLUSIONS: This study describes a neonate with PORD caused by three novel POR variants and expands the known clinical spectrum of PORD by identifying rare manifestations including anal atresia and hearing loss. RNA-seq provided valuable functional evidence for variant interpretation and facilitated accurate molecular diagnosis. These findings highlight the importance of integrating genetic phasing, transcript-level functional analysis, and comprehensive clinical evaluation for precise diagnosis and counseling in rare endocrine disorders.

Humans↗

PubMed2026

Deciphering the Role of LNX2 as a Potential Contributor to Neurodevelopmental Disorders.

BACKGROUND/OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition characterized by a complex and multifactorial genetic architecture. In this study, we report a male patient, born to non-consanguineous healthy parents, presenting with ADHD and oppositional defiant disorder (ODD). METHODS: Trio-based whole-exome sequencing (WES) was performed in the proband and both parents. Variant classification was performed according to American College of Medical Genetics and Genomics (ACMG) guidelines, and the potential pathogenicity of the identified variant was further assessed through multiple in silico prediction algorithms and protein structural analyses. RESULTS: WES identified a homozygous variant in the LNX2 gene (NM_153371.4: c.1165G>A, p.Ala389Thr), classified as a variant of uncertain significance (VUS) and supported by multiple in silico predictions. LNX2 is expressed during brain development and encodes an E3 ubiquitin ligase involved in neuronal differentiation and synaptic function. The identified variant is located within the PDZ2 domain, a functionally relevant region involved in protein-protein interactions. Although the variant is reported in population databases (gnomAD ID: rs148429804), it has not been associated with any clinical phenotype, and its presence in the homozygous state has been reported only once, remaining extremely rare and lacking clinical annotation. Structural modelling predicted localized rearrangement of the hydrogen-bonding network within the PDZ2 domain without major conformational changes. Integrative transcriptomic, and single-cell analyses further supported the biological relevance of LNX2 in neurodevelopment, highlighting its preferential association with neuronal projection-cell networks, synaptic vesicle trafficking pathways, and neuron-specific regulatory programs. CONCLUSION: Although the identified LNX2 variant cannot be considered causative for the patient's phenotype and a definitive disease-gene relationship cannot be established based on a single individual, the complementary genetic, structural, and transcriptomic findings support the biological plausibility of LNX2 as a candidate gene for neurodevelopmental disorders. Additional independent patients and functional studies will be required to clarify its contribution to human disease.

Child↗