AP4B1-associated hereditary spastic paraplegia: Expansion of clinico-genetic phenotype and geographic range.

BACKGROUND: Hereditary spastic paraplegias (HSP) are a group of neurodegenerative diseases that present with weakness and stiffness in the lower limb muscles and lead to progressive neurological decline. Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to complex HSP. This study aimed to identify causative genetic variants in consanguineous families with HSP from Azerbaijan and Pakistan. METHODS: We performed a thorough clinical and neuroradiological characterization followed by exome sequencing in 7 patients from 3 unrelated families. Segregation analysis was subsequently performed by Sanger sequencing. RESULTS: We describe 7 patients (4 males, 2-31 years of age) with developmental delay and spasticity. Similar to the previously reported cases with AP4B1-associated HSP, cases in the present report besides spasticity in the lower limbs had additional features including microcephaly, facial dysmorphism, infantile hypotonia, and epilepsy. The imaging findings included thin corpus callosum, white matter loss, and ventriculomegaly. CONCLUSION: In this study, we report 7 novel cases of HSP caused by bi-allelic variants in AP4B1 in Azerbaijani and Pakistani families. Our observations will help clinicians observe and compare common and unique clinical features of AP4B1-associated HSP patients, further improving our current understanding of HSP.

Biallelic loss of EMC10 leads to mild to severe intellectual disability.

The endoplasmic reticulum membrane protein complex subunit 10 (EMC10) is a highly conserved protein responsible for the post-translational insertion of tail-anchored membrane proteins into the endoplasmic reticulum in a defined topology. Two biallelic variants in EMC10 have previously been associated with a neurodevelopmental disorder. Utilizing exome sequencing and international data sharing we have identified 10 affected individuals from six independent families with five new biallelic loss-of-function and one previously reported recurrent EMC10 variants. This report expands the molecular and clinical spectrum of EMC10 deficiency, provides a comprehensive dysmorphological assessment and highlights an overlap between the clinical features of EMC10-and EMC1-related disease.

Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder.

Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying degrees of delay in language and gross motor development, early onset seizures, hypotonia, behavioral features, movement disorders, and facial dysmorphism. The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the previous cohorts, which underlines the importance of larger cohorts for the phenotype descriptions of rare genetic disorders.

Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy.

The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders. Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.