PSMF1 variants cause a phenotypic spectrum from early-onset Parkinson's disease to perinatal lethality by disrupting mitochondrial pathways.

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a new gene implicated in PD and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD and parkinsonism to perinatal lethality with neurological manifestations across 15 unrelated pedigrees with 22 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants impair mitochondrial membrane potential, dynamics and mitophagy in patient-derived fibroblasts. Additionally, we develop models of psmf1 knockdown Drosophila and Psmf1 conditional knockout mouse exhibiting age-dependent motor impairment, with diffuse gliosis in mice. These findings unequivocally link defective PSMF1 to early-onset PD and neurodegeneration and suggest mitochondrial dysfunction as a mechanistic contributor.

Application of Prenatal Whole Exome Sequencing for Structural Congenital Anomalies-Experience from a Local Prenatal Diagnostic Laboratory.

Fetal structural congenital abnormalities (SCAs) complicate 2-3% of all pregnancies. Whole-exome sequencing (WES) has been increasingly adopted prenatally when karyotyping and chromosomal microarray do not yield a diagnosis. This is a retrospective cohort study of 104 fetuses with SCAs identified on antenatal ultrasound in Hong Kong, where whole exome sequencing is performed. Molecular diagnosis was obtained in 25 of the 104 fetuses (24%). The highest diagnostic rate was found in fetuses with multiple SCAs (29.2%), particularly those with involvement of the cardiac and musculoskeletal systems. Variants of uncertain significance were detected in 8 out of the 104 fetuses (7.7%). Our study shows the utility of WES in the prenatal setting, and the extended use of the technology would be recommended in addition to conventional genetic workup.

Functional Evaluation and Genetic Landscape of Children and Young Adults Referred for Assessment of Bronchiectasis.

Bronchiectasis is the abnormal dilation of the airway which may be caused by various etiologies in children. Beyond the more recognized cause of bacterial and viral infections and primary immunodeficiencies, other genetic conditions such as cystic fibrosis and primary ciliary dyskinesia (PCD) can also contribute to the disease. Currently, there is still debate on whether genome sequencing (GS) or exome sequencing reanalysis (rES) would be beneficial if the initial targeted testing results returned negative. This study aims to provide a back-to-back comparison between rES and GS to explore the best integrated approach for the functional and genetics evaluation for patients referred for assessment of bronchiectasis. In phase 1, an initial 60 patients were analyzed by exome sequencing (ES) with one additional individual recruited later as an affected sibling for ES. Functional evaluation of the nasal nitric oxide test, transmission electron microscopy, and high-speed video microscopy were also conducted when possible. In phase 2, GS was performed on 30 selected cases with trio samples available. To provide a back-to-back comparison, two teams of genome analysts were alternatively allocated to GS or rES and were blinded to each other's analysis. The time for bioinformatics, analysis, and diagnostic utility was recorded for evaluation. ES revealed five positive diagnoses (5/60, 8.3%) in phase 1, and four additional diagnoses were made by rES and GS (4/30, 13%) during phase 2. Subsequently, one additional positive diagnosis was identified in a sibling by ES and an overall diagnostic yield of 10/61 (16.4%) was reached. Among those patients with a clinical suspicion of PCD (n = 31/61), the diagnostic yield was 26% (n = 8/31). While GS did not increase the diagnostic yield, we showed that a variant of uncertain significance could only be detected by GS due to improved coverage over ES and hence is a potential benefit for GS in the future. We show that genetic testing is an essential component for the diagnosis of early-onset bronchiectasis and is most effective when used in combination with functional tools such as TEM or HSVM. Our comparison of rES vs. GS suggests that rES and GS are comparable in clinical diagnosis.

Comprehensive analysis of recessive carrier status using exome and genome sequencing data in 1543 Southern Chinese.

Traditional carrier screening has been utilized for the detection of carriers of genetic disorders. Since a comprehensive assessment of the carrier frequencies of recessive conditions in the Southern Chinese population is not yet available, we performed a secondary analysis on the spectrum and carrier status for 315 genes causing autosomal recessive disorders in 1543 Southern Chinese individuals with next-generation sequencing data, 1116 with exome sequencing and 427 with genome sequencing data. Our data revealed that 1 in 2 people (47.8% of the population) was a carrier for one or more recessive conditions, and 1 in 12 individuals (8.30% of the population) was a carrier for treatable inherited conditions. In alignment with current American College of Obstetricians and Gynecologists (ACOG) pan-ethnic carrier recommendations, 1 in 26 individuals were identified as carriers of cystic fibrosis, thalassemia, and spinal muscular atrophy in the Southern Chinese population. When the >1% expanded carrier screening rate recommendation by ACOG was used, 11 diseases were found to meet the criteria in the Southern Chinese population. Approximately 1 in 3 individuals (35.5% of the population) were carriers of these 11 conditions. If the 1 in 200 carrier frequency threshold is used, and additional seven genes would meet the criteria, and 2 in 5 individuals (38.7% of the population) would be detected as a carrier. This study provides a comprehensive catalogue of the carrier spectrum and frequency in the Southern Chinese population and can serve as a reference for careful evaluation of the conditions to be included in expanded carrier screening for Southern Chinese people.

Invasive cerebral phaeohyphomycosis in a Chinese boy with CARD9 deficiency and showing unique radiological features, managed with surgical excision and antifungal treatment.

We report this rare case of cerebral phaeohyphomycosis in a previously healthy Chinese boy, who was found to have caspase recruitment domain family member 9 (CARD9) deficiency. Initial radiological features suggested a neoplastic cerebral lesion, while histopathological examination supplemented by internal transcribed sequencing (ITS) of cerebral tissue confirmed the diagnosis of phaeohyphomycosis. He was treated with intravenous (IV) liposomal amphotericin B and voriconazole, guided by plasma and cerebrospinal fluid (CSF) level monitoring at drug initiation. At the 1 year follow-up, the patient demonstrated near complete neurological and radiological recovery.