Meester-Loeys syndrome (MLS) is an X-linked connective tissue disorder caused by pathogenic BGN variants. We describe a family carrying a novel missense variant. The index male, initially diagnosed with Ehlers-Danlos syndrome, had joint hypermobility, multiple visceral artery aneurysms, and recurrent musculoskeletal problems. A brother of the proband had an aortic root aneurysm. Female carriers had no or only minor manifestations. Studies of the aortic wall were consistent with a dysregulation of the TGF-β/SMAD pathway and assays with reporter vectors revealed reduced canonical Wnt and TGF-β activity in cell lines expressing mutant biglycan. However, patients' dermal fibroblasts did not show consistent differences in the nuclear abundance of β-catenin or p-SMAD2/3 compared to cells from controls. This 3-generation family expands the genetic and phenotypic spectrum of MLS and underscores the importance of considering BGN testing in hypermobility syndromes to enable early surveillance and targeted management.

Hereditary musculoskeletal disorders, including OI, X-linked hypophosphatemia (XLH), and hypermobile Ehlers-Danlos syndrome (hEDS), are associated with significantly diminished quality of life (QoL) compared to the general population. Although the recognition of patient-reported outcomes (PROs) in clinical practice is growing, the specific factors that most profoundly influence QoL in these disorders, as well as the differences among them, remain poorly understood. The objective of this cross-sectional study was to examine the QoL in 142 adult patients with rare genetic disorders, focusing on pain intensity and pain-related limitations. Medical data from patient records were collected and analyzed statistically. QoL was assessed using generic questionnaires (BPI-SF, EQ-5D-5L, SF-36v2), and pain intensity along with related limitations were evaluated. The data were analyzed using SPSS software, with regression analyses conducted to identify factors associated with QoL. All patient groups reported pain, which was associated with a significantly reduced QoL. Among these groups, those with hEDS experienced the most severe impairment and reported the highest levels of pain. Meanwhile, patients with OI type III faced the most substantial limitations in physical functioning, whereas no significant differences could be found between OI type I and XLH. To improve overall QoL for individuals with OI, XLH, and hEDS, it is essential to implement multimodal pain management strategies, addressing not only physical pain but also psychological and social dimensions. Additionally, ongoing development and integration of PROs into clinical practice will enhance the understanding of how these conditions affect patients, guiding the creation of more effective, patient-centered interventions.

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder with progressive proximal weakness as the principal sign. Glucocorticoids and physical therapy are the mainstay of treatment. Exercise intolerance is the hallmark of metabolic myopathies, which require a combination of laboratory testing, electrodiagnostic testing, and muscle biopsy for diagnosis. Joint hypermobility may be an isolated finding or be associated with hypermobility Ehlers-Danlos syndrome (EDS), other variants of EDS, or marfanoid syndromes. The latter conditions are associated with aortic and cardiac valvular abnormalities. Osteogenesis imperfecta encompasses a group of disorders characterized by bone fragility presenting with a low-impact fracture as a result of minimal trauma. Management includes multidiscipline specialists. Down syndrome (DS), or trisomy 21, is the most common chromosome abnormality identified in live births. Routine evaluation of atlantoaxial instability with x-ray is no longer recommended for children with DS without symptoms of atlantoaxial instability; however, clinical evaluation of symptoms is required for sports preparticipation. Achondroplasia is the most common skeletal dysplasia. Clinical signs are macrocephaly, short limb, short stature with disproportionately shorter humerus and femur, along with characteristic findings in pelvis and lumbar spine x-rays. Caregivers should be educated on proper positioning and handling to avoid complications, including car seat-related deaths.

SINE-VNTR-Alu (SVA) retrotransposons move from one genomic location to another in a 'copy-and-paste' manner. They continue to move actively and cause monogenic diseases through various mechanisms. Currently, disease-causing SVA retrotransposons are classified into human-specific young SVA_E or SVA_F subfamilies. In this study, we identified an evolutionarily old SVA_D retrotransposon as a novel cause of occipital horn syndrome (OHS). OHS is an X-linked, copper metabolism disorder caused by dysfunction of the copper transporter, ATP7A. We investigated a 16-year-old boy with OHS whose pathogenic variant could not be detected via routine molecular genetic analyses. A 2.8 kb insertion was detected deep within the intron of the patient's ATP7A gene. This insertion caused aberrant mRNA splicing activated by a new donor splice site located within it. Long-read circular consensus sequencing enabled us to accurately read the entire insertion sequence, which contained highly repetitive and GC-rich segments. Consequently, the insertion was identified as an SVA_D retrotransposon. Antisense oligonucleotides (AOs) targeting the new splice site restored the expression of normal transcripts and functional ATP7A proteins. AO treatment alleviated excessive accumulation of copper in patient fibroblasts in a dose-dependent manner. Pedigree analysis revealed that the retrotransposon had moved into the OHS-causing position two generations ago. This is the first report of a human monogenic disease caused by the SVA_D retrotransposon. The fact that the evolutionarily old SVA_D is still actively transposed, leading to increased copy numbers may make a notable impact on rare genetic disease research.

Genetic variants in ATP7A are associated with a spectrum of X-linked disorders. In descending order of severity, these are Menkes disease, occipital horn syndrome, and X-linked distal spinal muscular atrophy. After 30 years of diagnostic investigation, we identified a deep intronic ATP7A variant in four males from a family affected to variable degrees by a predominantly skeletal phenotype, featuring bowing of long bones, elbow joints with restricted mobility which dislocate frequently, coarse curly hair, chronic diarrhoea, and motor coordination difficulties. Analysis of whole genome sequencing data from the Genomics England 100,000 Genomes Project following clinical re-evaluation identified a deep intronic ATP7A variant, which was predicted by SpliceAI to have a modest splicing effect. Using a mini-gene splicing assay, we determined that the intronic variant results in aberrant splicing. Sanger sequencing of patient cDNA revealed ATP7A transcripts with exon 5 skipping, or inclusion of a novel intron 4 pseudoexon. In both instances, frameshift leading to premature termination are predicted. Quantification of ATP7A mRNA transcripts using a qPCR assay indicated that the majority of transcripts (86.1 %) have non-canonical splicing, with 68.0 % featuring exon 5 skipping, and 18.1 % featuring the novel pseudoexon. We suggest that the variability of the phenotypes within the affected males results from the stochastic effects of splicing. This deep intronic variant, resulting in aberrant ATP7A splicing, expands the understanding of intronic variation on the ATP7A-related disease spectrum.