American Journal of Medical Genetics Part A最新文献

Osteogenesis imperfecta type VI is a rare genetic disorder caused by biallelic disease-causing variants in SERPINF1. The phenotype is characterized by severe osteopenia, recurrent fractures, and moderate to severe skeletal deformities. We report an 11-year-old individual who presented with multiple fractures of the long bones of the upper and lower extremities, severe osteopenia, and skeletal deformities. Whole exome sequencing revealed compound heterozygous variants c.[-37C>A];[829_831del] in SERPINF1. To determine the functional consequence of the variants, quantitative real-time PCR and immunoblotting analyses in patient-derived fibroblasts were performed, which showed reduced expression of SERPINF1 transcript and protein levels.

TSPEAR (chr. 21q22.3) encodes a protein involved in tooth development and is predominantly expressed in the enamel knot. Biallelic loss of function variants in TSPEAR cause ectodermal dysplasia, tooth agenesis and sensorineural hearing loss. However, the role of TSPEAR in auditory processes is unclear. This study aimed at better delineating the allelic and clinical spectrum of TSPEAR-associated disorders. We identified homozygous and compound heterozygous causative variants in TSPEAR [NM_144991.3] in 11 patients from seven families. Abnormalities in tooth number and shape (conical teeth and tooth agenesis with a variable number of missing teeth) were found in all affected individuals. Maxillary retrusion was present in 6/11. Manifestations in other ectodermal-derived organs were seen in a minority of patients. None of the individuals had hearing loss. We identified a total of 10 variants, of which seven have not been previously published, and analyzed the effect of missense variants to support their pathogenicity. Our results demonstrate that individuals with biallelic variants in TSPEAR show complete penetrance for dental manifestations, but not for other ectodermal abnormalities. TSPEAR-related disorder is more common than previously thought, while hearing loss is not a feature of the disease.

We describe a novel homozygous intragenic deletion in the ALS2 gene in an 8-year-old boy with Infantile-onset Ascending Hereditary Spastic Paraplegia (IAHSP) and oculomotor apraxia, thereby contributing to the expanding genetic landscape of ALS2-related disorders. Comprehensive neurological evaluation, chromosomal microarray analysis (CMA), and trio-based whole exome sequencing (WES) were performed. CMA revealed a run of homozygosity (ROH) at 2q33.1. WES identified a homozygous deletion encompassing exons 24-25 of ALS2, inherited from heterozygous parents. This clinical phenotype was consistent with the IAHSP spectrum, and no previous cases due to intragenic deletion have been reported. Our findings further expand the mutational spectrum of ALS2-related disorders and underscore the relevance of combining CMA and WES in the diagnostic workup of early-onset motor disorders, particularly in consanguineous families and unresolved cases. Greater awareness of rare intragenic deletions may improve early recognition and facilitate accurate genetic counseling in pediatric neurogenetics.

Neurometabolic diseases are a group of genetic disorders caused by defects in metabolic networks. To characterize the clinical, radiological, and molecular phenotype of three patients with variants in the NAXD gene, together with a review of the literature. A retrospective review of medical records was conducted. Three patients with chronic, progressive, recurrent encephalopathy triggered by fever were identified, with two clinically relevant variants in compound heterozygosity in the NAXD (NM_001242882.2) gene. Individuals 1 and 2: c.794_798dup and c.922C>T. Individual 3: c.269G>T and c.922C>T. We report three patients with neurometabolic disease characterized by recurrent progressive encephalopathy, developmental regression, and movement disorders, associated with systemic involvement and inflammatory-appearing central nervous system lesions due to NAXD enzymatic deficiency. The condition follows a febrile episode, often resulting in early mortality. Other cases showed recurrent episodes triggered by febrile events, characterized by encephalopathy, abnormal movements, ataxia, and seizures. The most frequent systemic manifestations included hematological, mucocutaneous, and cardiac involvement. These three patients broaden the clinical and molecular spectrum of NAXD-associated encephalopathy. Given its potential therapeutic implications, this condition should be considered in the differential diagnosis of neuroinflammatory diseases with poor outcomes, especially in cases with multisystem manifestations.

FRMPD4, a gene on the X-chromosome, encodes a neuronal scaffold protein, and six variants in this gene have been associated with X-linked neurodevelopmental disorder. We identified a novel intronic hemizygous variant (NM_014728.3:c.1198-6C>A) in FRMPD4 in a 2-year-old male patient with moderate developmental delay inherited from his asymptomatic heterozygous mother. Minigene assays in different cell lines demonstrated that this variant led to the consistent skipping of in-frame exon 12, which encodes 30 amino acids within the FERM domain. We speculated that this splicing defect may be due to the impaired recruitment of essential splicing factor U2AF2, as this C>A intronic variant is positioned at the center of the uridine-rich polypyrimidine tract, adjacent to the 3'-splice site. Structural modeling predicted that the loss of this region would disrupt the integrity of the FERM domain. Given that FRMPD4 mediates metabotropic glutamate receptor signaling via its FERM domain, we conclude that this intronic variant is likely pathogenic.

Mosaicism is relatively common in Tuberous Sclerosis Complex (TSC) but can be difficult to detect using routine diagnostic tests, particularly when the variant allele frequency (VAF) is low. We describe two cases of mosaic TSC diagnosed using an ultra-deep sequencing approach in multiple tissues and review the literature about this topic in order to discuss new diagnostic paradigms. In the first case, further testing was prompted by the presence of angiomyolipomas in the otherwise unaffected 51-year-old father of a woman diagnosed with TSC2; the familial pathogenic variant was present with a very low VAF in angiomyolipoma tissue and peripheral blood. The second case, a 17-year-old boy diagnosed with infantile myofibromatosis, presented dermatological and brain MRI findings suggestive of TSC; a TSC1 pathogenic variant was first identified on DNA extracted from angiofibroma biopsy, and then confirmed on non-lesional skin, peripheral blood, and saliva. The identification of the causative TSC1/2 variant is crucial to provide appropriate management and genetic counseling for family planning. Most mosaic individuals in the literature have cutaneous features of TSC; in the presence of an accessible lesion, we recommend considering a tissue biopsy to have a higher chance of identifying a low-level mosaicism.

Genetic testing using targeted panels or comprehensive genome sequencing is the current standard for diagnosing Duchenne muscular dystrophy (DMD), identifying pathogenic variants in up to 98% of cases. We report a 5-year-old male presenting with delayed motor milestones, frequent falls, and difficulty climbing stairs due to generalized muscle weakness. Laboratory studies revealed markedly elevated CK (13,041 U/L) and chronic transaminase elevation. Clinical examination demonstrated Gower's sign, calf pseudohypertrophy, neuromuscular scoliosis, and cognitive impairment. Initial neuromuscular gene panel testing identified several variants of uncertain significance, and muscle biopsy showed markedly reduced dystrophin labeling. Follow-up short-read DMD sequencing with deletion/duplication analysis at Age 11 remained negative. Given persistently negative findings, we utilized optical genome mapping (Bionano Genomics) and long-read sequencing (Oxford Nanopore Technologies) to identify potential structural variants. Both methods independently detected a novel inversion identified to span 31 kb and encompassing exons 68-73 of the DMD gene (ChrX: 31,171,362-31,202,982), classified as pathogenic. This case highlights a clinically definitive diagnosis of DMD missed by standard genetic testing. Our findings demonstrate that Optical Genome Mapping and Long-Read Sequencing provide complementary, high-resolution tools for identifying previously unidentified structural variants and should be considered in unresolved cases prior to invasive procedures such as muscle biopsy.