Genomic Analyses
A whole genome single nucleotide polymorphism (SNP) microarray was performed as a trio on the subject, mother, and father. A de novo2.62 Mb interstitial deletion of 6q22.l_q22.31 was detected, which is interpreted as pathogenic, as seen in Table 3 . This interval includes nine OMIM genes (VGLL2, ROSl, GOPC, NUSl, CEP85L, PLN, MCM9, ASFlA, MANlAl ). In addition, the microarray also identified a 1.16 mb interstitial duplication of 7p21.2_ p21.1 and 77 kb interstitial duplication of 22q12.1_q12.1 in the proband. This interval includes 6 OMIM genes (BZW2, TSPAN13, AGR2, AGR3, AHR, SNX13 ). At this time, no clinically established disorders have been reported with duplication of this region.
DI SCUSSION
The NUS 1 (nuclear undecaprenyl pyrophosphate synthase 1) gene encodes the Nogo-B receptor (NgBR), a subunit that is essential protein for dolichol synthesis. Dolichol serves as a carrier for the oligosaccharaide chain of N-linked glycosylation, which contributes to proper folding and quality control of proteins. (Chiu et al. 2007). In addition to cellular dolichol synthesis and protein glycosylation, NgBR is responsible for lysosomal cholesterol accumulation. Specifically, lysosomal cholesterol accumulation contributes to movement deficits associated with NUS1 haploinsufficiency (Yu et al. 2021). NUS1was among many candidate genes that were found to be associated with developmental and epileptic encephalopathy (DEE), a group of conditions characterized by co-occurrence of epilepsy and intellectual disability (Hamdan et al. 2017). A previous study reported six individuals with seizures and overlapping microdeletion on 6q22.1_q22.31, narrowing the critical region to 250 kb. This region encompasses NUS1 and the promoter of SLC35F1, which were important contributors to tremors and epilepsy (Szafranski et al. 2015). Variants of NUS1 have also been linked with ataxia (Den et al. 2019). In some less common cases,NUS1 contributes to parkinsonism, scoliosis, gestational diabetes mellitus, and psychosis (Den et al. 2019; Jiang et al. 2022; Fraiman et al. 2021). NUS1 is classically associated with Congenital Disorder of Glycosylation, Type Iaa, and autosomal dominant type 55 intellectual disability with seizures (Hamdan et al. 2017; Yu et al. 2021). So far, there have been reports of nine de novo NUS1variants linked to developmental and epileptic encephalopathy (Den, 2019). Individuals with congenital disorders of glycosylation are susceptible to a variety of different symptoms across several different organ systems, which include developmental delays, poor growth, nerve damage, endocrine dysfunction, and facial dysmorphism. There are over 130 different diseases linked to dysfunctions in the glycosylation pathway, many of which do not have any treatment (Chang, He, and Lam 2018). Although some congenital disorders of glycosylation can be found to have elevated oxysterols (Dang Do et al. 2023), this did not appear to be the case in our patients, perhaps suggesting that the intact copy of NUS1 on the other chromosome is sufficient to prevent substantial oxysterol accumulation.
ASF1A is a gene responsible for encoding a histone chaperone protein belonging to the H3/H4 family and regulates nucleosome assembly (Liang et al. 2017). All three studies reported in Clinvar that involveASF1A deletion have a variant length over 1kb involving multiple genes, making it difficult to attribute the connection betweenASF1A to the neurodevelopmental symptoms. VGLL2 is a gene that encodes for the transcription factor of vestigial-like protein 2 that is associated with skeletal muscle development (Hitachi et al. 2019). Variants including deletions in this gene had other genes deleted including NUS1 (Szafranski et al. 2015). Thus, the precise contribution of this gene or its lack thereof could not be determined. Similarly, GOPC is a gene that encodes a Golgi protein that could contribute to infertility (Bizkarguenaga et al. 2019). Variants in ClinVar included NUS1 and other genes, making it difficult to determine its contribution. Finally, ROS1 , a proto-oncogene that encodes for either a protein or differentiation factor could contribute to tumor development (Drilon et al. 2021). Additional variants withROS1 deletion included NUS1 and other genes and did show phenotypes of delayed speech and language development as well as intellectual disability. Thus, based on our search, the patient’s phenotype of seizures, tremors, intellectual disability, and delayed speech and language development seem to be more associated with aNUS1 mutation as opposed to the other OMIM genes.