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.