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Neurochondrin (NCDN) is a cytoplasmatic neural protein of importance for neural growth, glutamate receptor (mGluR) signaling, and synaptic plasticity. Conditional loss of Ncdn in mice neural tissue causes depressive-like behaviors, impaired spatial learning, and epileptic seizures. We report on NCDN missense variants in six affected individuals with variable degrees of developmental delay, intellectual disability (ID), and seizures. Three siblings were found homozygous for a NCDN missense variant, whereas another three unrelated individuals carried different de novo missense variants in NCDN. We assayed the missense variants for their capability to rescue impaired neurite formation in human neuroblastoma (SH-SY5Y) cells depleted of NCDN. Overexpression of wild-type NCDN rescued the neurite-phenotype in contrast to expression of NCDN containing the variants of affected individuals. Two missense variants, associated with severe neurodevelopmental features and epilepsy, were unable to restore mGluR5-induced ERK phosphorylation. Electrophysiological analysis of SH-SY5Y cells depleted of NCDN exhibited altered membrane potential and impaired action potentials at repolarization, suggesting NCDN to be required for normal biophysical properties. Using available transcriptome data from human fetal cortex, we show that NCDN is highly expressed in maturing excitatory neurons. In combination, our data provide evidence that bi-allelic and de novo variants in NCDN cause a clinically variable form of neurodevelopmental delay and epilepsy, highlighting a critical role for NCDN in human brain development., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Hereditary Spastic paraplegias (HSPs) are heterogeneous group of degenerative disorders characterized by progressive weakness and spasticity of the lower limbs, combined with additional neurological features. This study aimed to identify causative gene variants in two nonrelated consanguineous Pakistani families segregating HSP. Whole exome sequencing (WES) was performed on a total of five individuals from two families including four affected and one phenotypically normal individual. The variants were validated by Sanger sequencing and segregation analysis. In family A, a novel homozygous variant c.604G > A (p.Glu202Lys) was identified in the CYP2U1 gene with clinical symptoms of SPG56 in 3 siblings. Whereas, a previously reported variant c.5769delT (p.Ser1923Argfs*28) in the SPG11 gene was identified in family B manifesting clinical features of SPG11 in 3 affected individuals. Our combined findings add to the clinical and genetic variability associated with CYP2U1 and SPG11 variants highlighting the complexity of HSPs. These findings further emphasize the usefulness of WES as a powerful diagnostic tool., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Keratosis pilaris atrophicans (KPA) is a group of rare genodermatoses characterised by perifollicular keratosis and inflammation that progresses to atrophy and scars of the facial skin. Keratosis pilaris of extensor areas of limbs is a common associated finding. Most cases with KPA are sporadic and no consistent inheritance pattern has been documented., Methods: A large consanguineous Pakistani pedigree segregating autosomal recessive KPA of a mixed type was subject to autozygosity mapping and whole exome sequencing. Quantification of mRNA and protein levels was performed on fibroblasts from affected individuals. Cellular uptake of the low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) ligand α2-macroglobulin (α(2)M) was quantified using fluorescence confocal microscopy., Results: Genetic analyses identified a unique homozygous missense variant (K1245R) in the LRP1 in all affected family members. LRP1 encodes the LRP1, a multifunctional cell surface receptor with endocytic functions that belongs to the LDL receptor family. The LRP1 mRNA and LRP1 protein levels in fibroblasts of affected individuals were markedly reduced when compared with controls. Similarly, the LRP1-mediated cellular uptake of α(2)M was reduced in patient fibroblasts., Conclusions: This is the first report on LRP1 as a pathogenic gene for autosomal recessive KPA and keratosis pilaris. The inflammatory characteristics of the KPA entity in our family suggest a link to the immune-regulatory functions of LRP1., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)