Nardilysin (NRDC) plays a role in multiple cellular functions in diverse cellular compartments, including ectodomain shedding in the plasma membrane, as well as chaperoning a key Krebs cycle enzyme in mitochondria. We had previously reported limited clinical information from two individuals with homozygous frameshift variants in NRDC. With inclusion of previously published individuals, here we report 14 individuals (10 females, four males) from nine unrelated families carrying homozygous NRDC pathogenic variants. Common clinical features include severe to profound developmental delay/intellectual disability (12/12), microcephaly (13/13), prematurity (5/13), lethality in the first 3 years of life (9/14), seizures (7/11), joint contractures (4/8), eye/visual abnormalities (5/7), and abnormal brain imaging studies ranging from diffuse atrophy to lissencephaly (8/11). The identified variants include two splice, three frameshift, and three missense variants. RT-PCR from affected individual fibroblasts and a minigene assay in HEK293T cells demonstrate that the splice variants led to exon skipping of NRDC. To further investigate the pathogenicity of the variants in vivo, we used the Drosophila Nrdc (dNrdc) mutant model. dNrdc null mutants caused developmental lethality, which is fully rescued by wild-type human NRDC. Studies in the Drosophila dNrdc mutant models showed that both splice variants and frameshift variants cause severe loss of function, leading to lethality, whereas missense variants cause partial lethality and short lifespan, consistent with less severe phenotype. Our data establish that homozygous variants in NRDC are pathogenic, leading to highly lethal and severe neurodevelopmental disorder in humans.

Treatment approaches are lacking for Fukuyama congenital muscular dystrophy (FCMD), the second most common type of pediatric muscular dystrophy after Duchenne muscular dystrophy (DMD) in the Japanese population. Recent studies demonstrating the involvement of prostaglandin (PG) D2 in DMD progression has led to the development of novel inhibitors targeting hematopoietic PGD2 synthase. This study aimed to determine the role of PGD2 in FCMD etiology in 42 patients with FCMD and 77 healthy age-matched individuals. Concentrations of tetranor-PGDM and tetranor-PGEM, the metabolites of PGD2 and PGE2, respectively, and creatinine were measured in spot urine samples. Mean tetranor-PGDM/creatinine and tetranor-PGEM/creatinine concentrations and tetranor-PGEM/tetranor-PGDM ratio were significantly higher in patients with FCMD than the healthy controls (5.3 ± 2.1 and 30.9 ± 52.3 ng/mg creatinine and 6.8 ± 2.0 vs. 3.4 ± 0.3 and 9.5 ± 0.9 ng/mg creatinine and 3.2 ± 0.3, respectively; p = 0.0011, p < 0.0001 and p < 0.0001, respectively). These metabolites were increased in patients with typical and severe FCMD phenotypes than in those with the mild FCMD phenotype, indicating their correlation with disease severity. These results implicate that PGD2 and PGE2 play important roles in FCMD pathogenesis and that novel hematopoietic PGD2 synthase inhibitors and steroids used in DMD may also have therapeutic utility in FCMD.

Walker-Warburg Syndrome is a genetically heterogeneous disease with autosomal recessive inheritance characterized by brain and eye deformities, profound mental retardation, congenital muscular dystrophy, and early death. This case study demonstrates a mutation on chromosome 12q14 in the TMEM5 gene (RXYLT1; 605862), which encodes a transmembrane protein with glycosyltransferase function. We present a case of a full-term male baby delivered by Cesarean section due to macrocephaly. At birth, the newborn had hypotonia and respiratory distress, requiring mechanical ventilation. On examination the patient was found to have macrocephaly, generalized hypotonia, hyporeflexia, and retinal degeneration. Genetic testing revealed a homozygous variant in the RXYLT1 gene, consistent with the diagnosis of autosomal recessive muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A10. The patient underwent a ventriculoperitoneal shunt and received supportive management. WWS is a fatal disease, and most affected children do not survive beyond the age of 3. Prenatal screening, ultrasonography and magnetic resonance imaging can aid in the detection and confirmation of abnormal brain development in WWS cases.

PAFAH1B1, also known as LIS1, is associated with type I lissencephaly in humans, which is a severe developmental brain disorder believed to result from abnormal neuronal migration. Our objective was to characterize the genotypes and phenotypes of PAFAH1B1-related epilepsy. We conducted a comprehensive analysis of the medical histories, magnetic resonance imaging findings, and video-electroencephalogram recordings of 11 patients with PAFAH1B1 variants at the Neurology Department of Beijing Children's Hospital from June 2017 to November 2022. The age of onset of epilepsy ranged from 2 months to 4 years, with a median onset age of 5 months. Among these 11 patients (comprising 6 boys and 5 girls), all were diagnosed with lissencephaly type 1. Predominantly, generalized tonic-clonic and spasm seizures characterized PAFAH1B1-related epilepsy. Additionally, 10 out of the 11 patients exhibited severe developmental disorders. All patients exhibited de novo variants, with three individuals displaying 17p13.3 deletions linked to haploinsufficiency of PAFAH1B1. Four variants were previously unreported. Notably, three patients with 17p13.3 deletions displayed developmental delay and drug resistant epilepsy, whereas the single patient with mild developmental delay, Intelligence Quotient (IQ) 57 and well-controlled seizures had a splicing-site variant. The severity of the phenotype in patients with PAFAH1B1 variants ranged from drug-responsive seizures to severe epileptic encephalopathy. These observations underscore the clinical heterogeneity of PAFAH1B1-related disorders, with most patients exhibiting developmental disorders. Moreover, the severity of epilepsy appears to be linked to genetic variations.

Determine the incremental diagnostic yield of prenatal exome sequencing (pES) over chromosome microarray (CMA) or G-banding karyotype in fetuses with central nervous system (CNS) abnormalities. Data were collected via electronic searches from January 2010 to April 2022 in MEDLINE, Cochrane, Web of Science and EMBASE. The NHS England prenatal exome cohort was also included. Incremental yield was calculated as a pooled value using a random-effects model. Thirty studies were included (n = 1583 cases). The incremental yield with pES for any CNS anomaly was 32% [95%CI 27%-36%; I2 = 72%]. Subgroup analysis revealed apparent incremental yields in; (a) isolated CNS anomalies; 27% [95%CI 19%-34%; I2 = 74%]; (b) single CNS anomaly; 16% [95% CI 10%-23%; I2 = 41%]; (c) more than one CNS anomaly; 31% [95% Cl 21%-40%; I2 = 56%]; and (d) the anatomical subtype with the most optimal yield was Type 1 malformation of cortical development, related to abnormal cell proliferation or apoptosis, incorporating microcephalies, megalencephalies and dysplasia; 40% (22%-57%; I2 = 68%). The commonest syndromes in isolated cases were Lissencephaly 3 and X-linked hydrocephalus. Prenatal exome sequencing provides a high incremental diagnostic yield in fetuses with CNS abnormalities with optimal yields in cases with multiple CNS anomalies, particularly those affecting the midline, posterior fossa and cortex.