Identification of two novel heterozygous variants of SMC3 with Cornelia de Lange syndrome.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder, and cases caused by variants in the structural maintenance of chromosomes protein 3 (SMC3) gene are uncommon. Here, we report two cases of CdLS associated with novel pathogenic variants in SMC3 from two Chinese families. METHODS: Clinical presentations of two patients with CdLS were evaluated, and specimens from the patients and other family members were collected for Trio-based whole-exome sequencing. Pyrosequencing, chip-based digital PCR, minigene splicing assay, and in silico analysis were carried out to elucidate the impact of novel variants. RESULTS: Novel heterozygous variants in SMC3 were identified in each proband. One harbored a novel splicing and mosaic variant (c.2535+1G>A) in SMC3. The mutated allele G>A conversion was approximately 23.1% by digital PCR, which indicated that 46.2% of peripheral blood cells had this variant. Additionally, in vitro minigene splicing analysis validated that the c.2535+1G>A variant led to an exon skipping in messenger RNA splicing. The other carried a heterozygous variant (c.435C>A), which was predicted to be pathogenic as well as significantly altered in local electrical potential. The former showed multiple abnormalities and marked clinical severity, and the latter mainly exhibited a speech developmental disorder and slightly facial anomalies. CONCLUSION: Both patients were clinically diagnosed with Cornelia de Lange syndrome 3 (CdLS3). The newly identified SMC3 gene variants can expand the understanding of CdLS3 and provide reliable evidence for genetic counseling to the affected family.

Cost and health-related quality of life for children hospitalized with respiratory syncytial virus in Central China.

BACKGROUND: The economic burden of respiratory syncytial virus (RSV) infection and its impact on health-related quality of life (HRQoL) are not well-understood in China. This study assessed total cost and HRQoL for children hospitalized with RSV in Central China. METHODS: Based on a prospective case series study in Henan Province in 2020-2021, inpatients aged 0-59 months with RSV-related acute respiratory infections (ARIs) were included into analysis. Total cost included direct medical cost (sum of medical cost before and during hospitalization), direct non-medical cost, and indirect cost. Direct medical cost during hospitalization data were extracted from the hospital information system. Other costs and HRQoL status were obtained from a telephone survey conducted in the caregivers of the enrolled patients. RESULTS: Among 261 RSV-infected inpatients, caregivers of 170 non-severe cases (65.1%, 170/261) were successfully interviewed. Direct medical cost per episode was 1055.3 US dollars (US$) (95% CI: 998.2-1112.5 US$). Direct non-medical cost and indirect cost per episode were 83.6 US$ (95% CI: 77.5-89.7 US$) and 162.4 US$ (95% CI: 127.9-197.0 US$), respectively. Quality adjusted life years (QALY) loss for non-severe RSV hospitalization was 8.9 × 10-3 (95% CI: 7.9 × 10-3 -9.9 × 10-3 ). The majority of inpatients were <1 year of age comprising significantly higher cost and more QALY loss than older children. CONCLUSIONS: RSV-associated hospitalization poses high economic and health burden in Central China particularly for children <1 year old. Our findings are crucial for determining the priority of interventions and allocation of health resources.

[Clinical and genetic analysis of two rare male patients with Rett syndrome].

OBJECTIVE: To conduct clinical and genetic analysis of two male patients with atypical Rett syndrome. METHODS: Collection of clinical data in the two patients and these parents; whole exome sequencing (WES) was used to detect the potential variants, which were verified by Sanger sequencing. X chromosome inactivation (XCI) detection is performed in the Patient 1's mother to detect the allelic expression difference of the MECP2 gene. RESULTS: Patient 1, a 5-year and 10-month-old boy, had mental disorders and mild intellectual disability (ID) (IQ: 54), whose mother had ID. Patient 2 was a 9-month and 18-day-old male presented with recurrent infections, respiratory insufficiency, hypotonia and global developmental delay. WES indentified a hemizygous mutation, c.499C>T (p.R167W), in the MECP2 gene in patient 1, which was inherited from his mother. The inactivation of X chromosome is skewed, and the expression ratio of wild-type and mutant MECP2 is 100%:0. Patient 2 was found a de novo splicing mutation, c.62+2_62+3del in the MECP2 gene. They were both reported pathogenic variant related to Rett syndrome. c.499C>T (p.R167W) was defined as likely pathogenic (PS1+PM2+PP3) and c.62+2_62+3del was pathogenic (PVS1+PM2+PM6) based on American College of Medical Genetics and Genomics standards and guidelines. CONCLUSION: Both the two patients were diagnosed with rare male Rett syndrome, which had atypical clinical manifestations and large difference. Above foundings have revealed novel phenotypes in Chinese male patients with Rett syndrome.