Search Results (6)

Hypophosphatasia (HPP) is a rare hereditary metabolic disorder caused by nucleotide variants (NVs) in the ALPL gene, leading to a deficiency of tissue-nonspecific alkaline phosphatase (TNSALP). HPP has a variable clinical presentation (such as impaired mineralization of bones and teeth, respiratory dysfunctions, muscle weakness, muscle and bone pain, growth deficiency, nephrocalcinosis, seizures, encephalopathy, intracranial hypertension, and intellectual disability) overlapping with other disorders which often delays a correct diagnosis. In this study, we present the results of a two-center (Moscow and Saint Petersburg) selective screening program conducted in the period 2022–2026 in Russia, based on next-generation sequencing (NGS) of 4912 patients with suspected HPP. Each center used its own NGS gene panel. In Moscow, causal nucleotide variants in ALPL were found in 9.45% of patients, and variants in other genes from the panel were identified in 9.77% of patients. The selection criteria for the screening evolved during the study, resulting in a higher diagnostic yield. In Saint Petersburg, causal variants in ALPL were found in 3.5% of patients. The most frequent ALPL variant was c.571G>A (28%), which is consistent with its founder effect in Northern Europe. In the differential diagnosis gene panel, pathogenic or likely pathogenic variants were most commonly found in the COL1A2, COL1A1, and CASR genes, highlighting the phenotypic overlap of HPP with osteogenesis imperfecta and related disorders, and underscoring the value of targeted NGS for resolving diagnostic uncertainty in HPP. Overall, this study provides the most comprehensive data on the genetics of HPP in the Russian population to date. Full article

Background/Objectives: Arthrochalasia Ehlers–Danlos syndrome (aEDS) is a rare connective tissue disorder characterized by severe joint hypermobility, congenital hip dislocation, skin hyperextensibility, and muscle hypotonia. It is typically caused by heterozygous splice-site variants in COL1A1 or COL1A2, leading to exon 6 skipping. Autosomal recessive forms are extremely rare and have been reported predominantly in families from Saudi Arabia carrying the homozygous COL1A1 missense variant c.2050G>A, p.(Glu684Lys), with clinical presentations ranging from severe to mild. Methods: Clinical and molecular genetic evaluation of the patient was performed. Whole-exome sequencing was carried out, followed by confirmatory Sanger sequencing in the proband and both parents. Results: A 10-month-old boy presented with severe congenital hypotonia, bilateral hip dislocation, generalized joint hypermobility, skin hyperextensibility and craniofacial dysmorphism. A homozygous likely pathogenic variant NM_000088.4:c.2050G>A, p.(Glu684Lys) was identified in exon 31 of COL1A1; both healthy parents were confirmed to be heterozygous carriers of this variant. To our knowledge this is the first reported case in the Russian population and one of the few cases described worldwide of an autosomal recessive arthrochalasia-like EDS phenotype. Conclusions: This case further refines the phenotypic characterization associated with the recurrent homozygous COL1A1 p.(Glu684Lys) variant, demonstrating an arthrochalasia-like EDS phenotype of intermediate severity between the severe neonatal form with respiratory distress and recurrent fractures and the classical EDS. It further highlights the importance of considering collagenopathies in the differential diagnosis of congenital hypotonia, particularly in cases initially suggestive of neuromuscular disorders. Full article

Muscle biopsy has long been regarded as the cornerstone for diagnosing pediatric muscular disorders; however, it is invasive and may be limited by sampling error and inconclusive histopathological findings. This study aimed to evaluate whether whole-exome sequencing (WES) can effectively replace muscle biopsy as a first-line diagnostic approach in children with suspected neuromuscular disorders. Between January 2018 and December 2025, we prospectively enrolled 47 pediatric patients presenting with clinical features suggestive of muscular disorders at a tertiary medical center in Taiwan. The cohort included patients with suspected muscular dystrophies (n = 21), congenital myopathies (n = 23), and multiplex ligation-dependent probe amplification (MLPA)-negative Duchenne muscular dystrophy (DMD; n = 3). All patients underwent WES as the initial diagnostic test without prior muscle biopsy. Trio-based analysis using parental samples was performed in 29.8% of cases. Variant interpretation followed the American College of Medical Genetics and Genomics (ACMG) guidelines. WES identified a definitive molecular diagnosis in 72.3% of patients (34/47). Diagnostic yields varied by subgroup: 100% (3/3) in MLPA-negative DMD, 71.4% (15/21) in muscular dystrophies, and 69.6% (16/23) in congenital myopathies. Pathogenic or likely pathogenic variants were detected in 31 distinct genes, including COL6A1 and COL6A3, which are associated with Ullrich congenital muscular dystrophy. Notably, 58.8% of diagnosed patients (20/34) received molecular diagnoses that differed from their initial clinical impression, encompassing conditions such as ZSWIM6-associated neurodevelopmental disorders, GJB2-related hearing loss, OCRL-associated Lowe syndrome, and various metabolic or syndromic disorders. In all three MLPA-negative DMD cases, WES identified point mutations amenable to mutation-specific therapies. No patient required a muscle biopsy for diagnostic confirmation during the study period. First-tier WES demonstrates high diagnostic utility in pediatric muscular disorders while avoiding invasive muscle biopsy. The high rate of diagnostic reclassification underscores the substantial phenotypic overlap between primary neuromuscular diseases and other neurological or systemic conditions. These findings support the early implementation of genetic testing to enable accurate diagnosis and timely initiation of targeted therapies. Full article

Background: Type I collagen is the most abundant protein of the extracellular matrix. Pathogenic variants in COL1A1 or COL1A2 are classically associated with osteogenesis imperfecta (OI) and Ehlers–Danlos syndrome (EDS). An emerging clinical entity—COL1-related overlap disorder—encompasses individuals exhibiting phenotypic features of both conditions. Methods: We report a 55-year-old male presenting with disproportionate short stature, grayish-blue sclerae, multiple fractures, long bone deformities, joint hypermobility, and atrophic surgical scarring. The patient also had long-standing, untreated childhood-onset hypopituitarism. Imaging studies revealed numerous prior fractures, bowing of forearm bones, and multiple Wormian bones. Results: Genetic testing confirmed a novel heterozygous COL1A1 exon 14 variant (c.940G > A, p.Gly314Arg), presenting with a phenotype consistent with a COL1-related overlap syndrome. Conclusions: This case expands the phenotypic spectrum of COL1A1 mutations and supports the concept of COL1-related phenotypic overlap. Full article

Recently, an autosomal recessive subtype of connective tissue disorder within the spectrum of Ehlers–Danlos syndrome (EDS), named classical-like EDS type 2 (clEDS2), was identified. clEDS2 is associated with biallelic variants in the adipocyte enhancer binding protein 1 (AEBP1) gene, specifically, affecting its aortic carboxypeptidase-like protein (ACLP) isoform. We described the 15th patient (13th family) diagnosed with clEDS2. This patient presented with notable similarities in phenotype to the documented cases, along with additional characteristics such as significant prematurity and short stature. An EDS sequencing panel-based analysis revealed homozygous AEBP1: NM_001129.5:c.2923del, p.Ala975Profs*22 likely pathogenic variants, and maternally inherited heterozygous COL11A1: NM_001854.4:c.1160A>G, p.Lys387Arg variant of uncertain significance in our patient. Upon comprehensive review of all previously reported clEDS2 patients, our patient exhibited the following overlapping phenotypes, including cutaneous features: hyperextensibility, atrophic scars/delayed wound healing (100%), easy bruising (100%), excessive skin (93%); skeletal features: generalized joint hypermobility (93%), pes planus (93%), dislocation/subluxation (93%); and cardiovascular features (86%). Our patient did not display symptoms of the critical complications reported in a few individuals, including superior mesenteric artery aneurysms and ruptures, aortic root aneurysm/dissection, spontaneous pneumothoraxes, and bowel ruptures. Together, this case expands the genetic and clinical phenotypic spectrum of AEBP1-related clEDS2. Full article

Loneliness and social isolation are detrimental to mental health and may lead to cognitive impairment and neurodegeneration. Although several molecular signatures of loneliness have been identified, the molecular mechanisms by which loneliness impacts the brain remain elusive. Here, we performed a bioinformatics approach to untangle the molecular underpinnings associated with loneliness. Co-expression network analysis identified molecular ‘switches’ responsible for dramatic transcriptional changes in the nucleus accumbens of individuals with known loneliness. Loneliness-related switch genes were enriched in cell cycle, cancer, TGF-β, FOXO, and PI3K-AKT signaling pathways. Analysis stratified by sex identified switch genes in males with chronic loneliness. Male-specific switch genes were enriched in infection, innate immunity, and cancer-related pathways. Correlation analysis revealed that loneliness-related switch genes significantly overlapped with 82% and 68% of human studies on Alzheimer’s (AD) and Parkinson’s diseases (PD), respectively, in gene expression databases. Loneliness-related switch genes, BCAM, NECTIN2, NPAS3, RBM38, PELI1, DPP10, and ASGR2, have been identified as genetic risk factors for AD. Likewise, switch genes HLA-DRB5, ALDOA, and GPNMB are known genetic loci in PD. Similarly, loneliness-related switch genes overlapped in 70% and 64% of human studies on major depressive disorder and schizophrenia, respectively. Nine switch genes, HLA-DRB5, ARHGAP15, COL4A1, RBM38, DMD, LGALS3BP, WSCD2, CYTH4, and CNTRL, overlapped with known genetic variants in depression. Seven switch genes, NPAS3, ARHGAP15, LGALS3BP, DPP10, SMYD3, CPXCR1, and HLA-DRB5 were associated with known risk factors for schizophrenia. Collectively, we identified molecular determinants of loneliness and dysregulated pathways in the brain of non-demented adults. The association of switch genes with known risk factors for neuropsychiatric and neurodegenerative diseases provides a molecular explanation for the observed prevalence of these diseases among lonely individuals. Full article