Molecular Syndromology最新文献

Introduction: X-linked intellectual developmental disorder 99 (XLID99) is a rare neurodevelopmental disorder associated with mutations in the USP9X gene. This study reports on 3 patients diagnosed with autism spectrum disorder (ASD), highlighting novel genetic findings.

Case presentation: Among the 3 patients, two male siblings exhibited a novel USP9X gene missense variant, while the third, a female, presented a unique deletion of the USP9X gene alongside adrenal insufficiency and mosaic Turner syndrome. This variant has not been reported in public databases and may influence ASD development.

Conclusion: This report documents the first instance of a triple diagnosis of XLID99, Turner syndrome, and congenital adrenal hyperplasia. Findings underline the significance of genetic evaluation in ASD for identifying rare and complex diagnoses.

Introduction: Dyskeratosis congenita is a hereditary short telomere syndrome that is characterized by dysplastic nails, reticular pigmentation, oral leucoplakia and may have other progressive systemic manifestations. Here, we report two affected siblings in a family with dyskeratosis congenita.

Case presentation: A two-year-old girl (index patient) was admitted to our hospital with complaints of inability to walk and decreased vision, as well as developmental delay and cataracts. Her parents were consanguineous, and she had an 18-year-old brother with cataracts, intellectual disability, liver cirrhosis, pancytopenia, and hypersplenism. Magnetic resonance imaging of the brain of the index case revealed hypointense foci in the bilateral basal ganglia, thalamus, and parietal white matter, while the results of detailed metabolic tests were unremarkable. After 8 years of follow-up, the index patient was identified with additional findings that included intellectual disability, liver disease, pancytopenia, nail dystrophy, multiple foci of calcification on magnetic resonance imaging of the brain, while over the past 2 years, her brother developed nail dystrophy, oral leucoplakia, graying hair, and reticular pigmentation on his neck. Genome sequencing revealed a c.415T>C (p.Tyr139His) disease-causing variant in the NHP2 gene in the index case that was heterozygous in the parents and homozygous in the index case and her older brother.

Conclusions: In cases of multisystem involvement, consanguineous marriage, and multiple affected family members, patients may develop very rare diseases, such as dyskeratosis congenita, and physicians should be aware that new clinical findings may emerge during long-term follow-up, the diagnosis of which may count on genome sequencing.

Introduction: Ring chromosomes generally result from the fusion of breaks at the ends of both arms of a chromosome, typically leading to the loss of genetic material from these ends.

Case presentation: We report the case of a four-year-old patient who exhibits multiple café-au-lait spots, hypochromic spots, bitemporal narrowing, bilateral epicanthus, patent foramen ovale, and multiple brain abnormalities identified through magnetic resonance imaging. Karyotyping revealed a ring chromosome: r(12). Chromosomal microarray analysis revealed a ∼3.6 Mb deletion in the short arm and a ∼1.2 Mb deletion in the long arm of chromosome 12. The patient's phenotype is consistent with these genetic imbalances. To investigate ring chromosome instability and mosaicism, 200 metaphases were analyzed using G-banding and FISH with a whole chromosome painting probe, identifying 166 cells with a 46,XX,r(12) karyotype, 20 cells with monosomy 12, eight with a dicentric ring chromosome, three with two monocentric rings, two with two interlocked dicentrics, and one with an open ring chromosome.

Conclusion: This study provided a detailed characterization of the ring rearrangement of chromosome 12, the first with SNP array, enhancing the understanding of its genetic and phenotypic implications and contributing to expanding knowledge about this condition. Additionally, the findings can aid in better understanding the patient's prognosis, clinical follow-up, and genetic counseling.

Introduction: Meckel-Gruber syndrome (MKS) is a clinically and genetically heterogeneous ciliopathy characterized by a triad of occipital encephalocele, polycystic kidneys, and postaxial polydactyly. Almost all of them are lethal in the prenatal or first postnatal periods. It is usually diagnosed clinically with a detailed prenatal ultrasound examination. Variants have been reported in at least 14 different genes.

Case presentation: We report a male fetus with oligohydramnios, large kidneys with microcysts covering the entire abdomen, postaxial polydactyly of the hands, bilateral pes equinovarus, encephalocele, microphthalmia, short extremities, and a mass lesion under the diaphragm. Termination was recommended to the family due to severe findings. Fetal skin biopsy and parental peripheral blood samples were obtained to investigate the potential pathogenic variants associated with MKS via clinical exome sequencing and Sanger sequencing.

Conclusion: The fetus was homozygous for the c.16del (p.Leu6SerfsTer15) variant in the TCTN1 (NM_001082538.3), and both parents were heterozygous for the variant. Genetic diagnosis is very important in terms of counseling for subsequent pregnancies. To our knowledge, this is the third Meckel-Gruber case in the literature caused by the TCTN1, and a novel likely pathogenic variant was detected.

Introduction: Kniest dysplasia is a severe form of type II collagenopathy caused by mutations in collagen II alpha 1 chain (COL2A1) gene. It can be diagnosed in early childhood based on the clinical findings of short stature, splayed epiphysis, narrowed joint spaces and platyspondyly associated with maxillofacial, ophthalmological, and otolaryngological complications. Missense mutations and small deletions owing to exon skipping in the triple-helical region of COL2A1 have been reported in most cases of Kniest dysplasia.

Case presentation: We describe a female patient aged 39 years with difficulty in walking, back pain, and limited movement of the lower extremities. She had experienced neck pain during adolescence; however, it gradually decreased with age. She also showed markedly short stature (-4.37 SD), cleft palate, cataract, retinal detachment, and serous otitis media. Radiographic analyses revealed epiphyseal enlargement of the longitudinal bones, kyphoscoliosis, and flat vertebrae in the thoracolumbar spine. The cervical spinal bodies were fused but not at the age of 19 years. Genetic analysis revealed a novel heterozygous mutation, c.1266+2T>A, in intron 20 of COL2A1. In silico predictive tools indicated that this mutation was pathological. Exon-trapping assay showed that this splice mutation led to both intron retention and exon skipping in the triple-helical region. These clinical findings and genetic tests confirmed the diagnosis of Kniest dysplasia.

Discussion: The diagnosis of Kniest dysplasia is sometimes difficult based on clinical findings in adulthood owing to progressive skeletal changes. The current novel splice mutation in COL2A1 demonstrates both out-of-frame transcript and in-frame deletion in Kniest dysplasia.

Introduction: Current guidelines recommend broad sequencing as a first-tier test for epilepsy, identifying a genetic etiology in 40% of cases. Sequencing subsequently increases the number of patients identified with variants of uncertain significance (VUSs). Clinicians desire additional investigatory methods to better classify these VUSs.

Case presentation: The HNRNPU gene (MIM #602869) is associated with a neurodevelopmental condition characterized by intellectual disability and developmental delay, epilepsy, and characteristic facial features. To date, only de novo variants with complete penetrance have been described. We present a 7-year-old female with HNRNPU variant c.669_691dup; p.Gly231Valfs*116, classified as both pathogenic (Laboratory A) and as a VUS (Laboratory B). This patient exhibits an isolated seizure phenotype, and familial studies revealed the proband's father (asymptomatic), paternal uncle (epilepsy), and paternal grandmother (asymptomatic) all carry this variant. Laboratory B theorized the potential for alternative splicing, reducing concerns about pathogenicity. Methylation studies were pursued for more accurate classification and are conclusively negative for the HNRNPU episignature. This, in the context of the variant not segregating with the familial epilepsy phenotype, indicates a benign classification for the c.669_691dup; p.Gly231Valfs*116 variant.

Conclusion: The number of epilepsy patients with nondiagnostic genetic results requires additional modes of investigation. Reclassification often takes years due to the novelty of variants identified. This case highlights the importance of laboratory scrutiny when multiple variants are detected, the need for greater data sharing between laboratories to reduce inconsistent classifications, and the utility of ancillary testing, such as methylation studies, to aid in VUS reclassification.

Introduction: Neonatal severe hyperparathyroidism (NSHPT) is a rare but life-threatening disorder caused by inactivating variants in the calcium-sensing receptor (CASR), resulting in severe hypercalcemia during the neonatal period. Infants with NSHPT may present with severe hypercalcemia, hyperparathyroidism, growth retardation, and respiratory distress. If untreated, NSHPT can lead to life-threatening complications. Due to its rarity, few cases have been reported in the literature.

Case presentation: A 4-day-old girl presented with jaundice, weight loss, and hypercalcemia (16 mg/dL). On physical examination, she appeared dehydrated and hypotonic, and had facial dysmorphisms. Laboratory results revealed markedly elevated parathyroid hormone levels (1,769 pg/mL) and low urinary calcium excretion. Despite initial treatment with hydration and furosemide, her hypercalcemia persisted. Cinacalcet was started but failed to control calcium levels, leading to the need for a subtotal parathyroidectomy at 2.5 months of age. Genetic testing identified a homozygous mutation in the CASR gene (p.Met741LeufsTer24). Postoperatively, the patient developed hypocalcemia due to hungry bone syndrome and later experienced recurrent hypercalcemia, which was managed with pamidronate followed by calcitriol. At 21 months of age, she remains normocalcemic on daily calcitriol.

Conclusion: This case highlights the challenges in managing NSHPT, especially in cases resistant to medical treatment. Subtotal parathyroidectomy proved essential for controlling hypercalcemia. Continued documentation of NSHPT cases will help improve treatment strategies and outcomes for this rare condition.

Introduction: This is a preliminary study to investigate a feasible genotype-phenotype correlation by defining ophthalmological findings in different genotypes of Down syndrome (DS).

Methods: The study included 62 eyes of 31 DS patients. Patients were further subgrouped according to cytogenetic forms of DS. A comprehensive ophthalmological examination was performed and, biometric, keratometric, and pachymetric parameters were evaluated.

Results: The mean best-corrected visual acuity (BCVA) of trisomy 21 was 0.41 ± 0.14 (0.1-0.6) and was 0.6 ± 0.09 (0.5-0.7) for both mosaic and translocation trisomy 21 (p = 0.004). While 6 of the trisomy 21 patients (24%), 2 of the mosaic patients (66.7%), and all of the three translocation type patients had a normal accommodation response, the remaining patients had accommodation lags (p = 0.013).

Conclusions: Lens opacities and fundus abnormalities were more common in trisomy 21 (p < 0.001). The angle kappa was larger in trisomy 21 and smallest in the translocation trisomy 21 (p = 0.014). K₂ and corneal apex curvature were highest in trisomy 21 (p = 0.05 and p = 0.006, respectively). BCVA and accommodation response were reduced whereas lenticular opacities and fundus abnormalities were more common in trisomy 21. In addition, central cornea was steeper and angle kappa was larger. Further studies with larger cohorts would display differences among subgroups of cytogenetic abnormality.

Introduction: Osteogenesis imperfecta (OI) comprises a heterogeneous group of skeletal dysplasias characterized mainly by bone fragility and propensity to fractures. The most common forms include classic types I, II, III, and IV, according to the classification of Sillence, caused by variants in the COL1A1 or COL1A2 genes. This report describes a case series of patients with OI type I confirmed by whole genome sequencing, highlighting the clinical and radiological manifestations of one atypical family.

Case presentation: Six individuals (1M:5F), aged 8 months to 34 years at their first consultation, were enrolled. All were clinically classified as OI type I due to the presence of osteopenia associated with blue sclerae and bone fractures; four presented with short stature, two with hearing loss, and one with fragile teeth; molecular testing confirmed that all presented with heterozygous pathogenic or likely pathogenic variants in the COL1A1 gene. In one family, an unusual presentation was observed in the patient and her daughter, both of whom presented with severe short stature (Z-score <-6), abnormal skull shape (bathrocephaly), codfish vertebrae, bowing of the long bones in the lower limbs, and serpentine fibulas.

Conclusion: Bathrocephaly and serpentine fibula are rarely reported in classical OI types and are more frequently associated with other skeletal dysplasias, such as Hajdu-Cheney syndrome. This case report highlights the importance of recognizing underrated manifestations in OI and underscores the need for molecular confirmation.

Introduction: ATP1A3-related disorders encompass a clinically heterogeneous spectrum that includes previously defined dominantly inherited phenotypes such as alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome, as well as more complex and overlapping presentations.

Case presentation: In this study, we present 2 pediatric cases that expand the phenotypic and genotypic spectrum of ATP1A3-associated disease. Both patients presented with "Guillain-Barré syndrome (GBS)-like episodes" characterized by acute-onset encephalopathy, ataxia, areflexia, and sensorimotor deterioration following febrile infections. Prominent paroxysmal postural abnormalities and dystonia were noted in both cases; however, the overall clinical features blurred the classical boundaries between CAPOS and other ATP1A3-associated phenotypes. The first patient carried the previously reported heterozygous ATP1A3(NM_001256214.2):c.2491G>A(p.Glu831Lys) variant, classically associated with CAPOS, and also exhibited sensorineural hearing loss with a positive family history. The second patient harbored a novel ATP1A3(NM_152296.5):c.2266C>T p.(Arg756Cys)(Clinvar: VCV000425189.38) variant and displayed oculomotor apraxia and chorea during episodes.

Conclusion: These cases underscore the importance of considering ATP1A3 variants in children presenting with GBS-like features, infection-triggered neurological attacks, and mixed movement disorders. Our findings highlight the diagnostic value of genetic testing in atypical neuroregression syndromes and contribute to the recognition of "blended" ATP1A3 phenotypes beyond classical diagnostic entities. The novel pathogenic variant further supports ongoing efforts to refine genotype-phenotype correlations within this evolving group of neurological disorders.