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\begin{document}

\title{Novel Copy Number Deletion involving NUS1 associated with Epilepsy,
Tremor, and Intellectual Disability}



\author[1]{Gholson Lyon}%
\author[2]{Jing Y. Hsu}%
\author[2]{Daniah H. Ibrahim}%
\author[2]{Riza Ali}%
\author[1]{Elaine Marchi}%
\author[3]{Maureen Gavin}%
\author[3]{Karen Amble}%
\affil[1]{Institute for Basic Research Department of Human Genetics}%
\affil[2]{Rosalind Franklin University of Medicine and Science Chicago Medical School}%
\affil[3]{New York State Institute for Basic Research in Developmental Disabilities}%


\vspace{-1em}



  
  \date{June 15, 2024}


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\selectlanguage{english}
\begin{abstract}
Copy number variations (CNVs), among other genetic abnormalities, have
been implicated in a range of disorders and can result in a variety of
clinical manifestations, such as intellectual disability, developmental
disorders, and cancer. The role of specific genes within such CNVs,
especially novel or rare genes, is the subject of ever-advancing%
\end{abstract}%



\sloppy


\textbf{Article Title:} Novel Copy Number Deletion involving \emph{NUS1}
associated with Epilepsy, Tremor, and Intellectual Disability

\textbf{Running Title:} \emph{NUS1} Deletion with Epilepsy, Tremor, and
ID

\textbf{Authors:} Jing Y. Hsu\textsuperscript{1,2}, Daniah H.
Ibrahim\textsuperscript{1.2}, Riza Ali\textsuperscript{1,2}, Elaine
Marchi\textsuperscript{2}, Maureen Gavin\textsuperscript{3}, Karen
Amble\textsuperscript{3}, Gholson J. Lyon\textsuperscript{2, 3, 4}

\textsuperscript{1}Rosalind Franklin University of Medicine and Science,
Chicago, United States of America

\textsuperscript{2}Department of Human Genetics, New York State
Institute for Basic Research in Developmental Disabilities, Staten
Island, New York, United States of America

\textsuperscript{3}George A. Jervis Clinic, New York State Institute for
Basic Research in Developmental Disabilities, Staten Island, New York,
United States of America

\textsuperscript{4}Biology PhD Program, The Graduate Center, The City
University of New York, New York, United States of America

\textbf{Corresponding Author:~}

Gholson J. Lyon

Email: gholsonjlyon@gmail.com

\textbf{ABSTRACT}

Copy number variations (CNVs), among other genetic abnormalities, have
been implicated in a range of disorders and can result in a variety of
clinical manifestations, such as intellectual disability, developmental
disorders, and cancer. The role of specific genes within such CNVs,
especially novel or rare genes, is the subject of ever-advancing
contemporary genetics research. The identification and characterization
of these genes play an important role in understanding the
pathophysiology of many different medical conditions and shed light on
diagnosis refinement and different strategies for treatment. This case
study looks at the genetics underlying the clinical presentation in a
patient exhibiting epilepsy, spinal abnormalities, and intellectual
disability, with a focus on identifying the underlying genetic basis for
this presentation. Here we show a novel de novo 2.62 Mb interstitial
deletion at 6q22.1\_q22.31 implicates the \emph{NUS1} gene as a
significant contributor to the observed phenotypes. NUS1 classically has
been associated with congenital disorders of glycosylation and
intellectual disability. However, our findings regarding this deletion
suggest a broader phenotypic spectrum for \emph{NUS1} variants,
encompassing manifestations like kyphosis, choreoathetosis, and possible
dyskinesias, which were not notably linked to this gene before. This
paints a clearer picture of \emph{NUS1} 's clinical relevance beyond
previously known links. The results of this report also add to the
building body of evidence that highlights the significance of CNVs in
neurological and developmental disorders. Our findings reinforce the
importance of genetic analysis in patients presenting with atypical
symptoms.

\textbf{CASE PRESENTATION}

\textbf{Clinical Presentation and Family History}

The subject is a 33-year-old man presenting with mild-to-moderate
intellectual disabilities; the family has spent a lifetime on an odyssey
to understand the subject's condition and to collaborate with clinicians
to develop a best treatment strategy. The subject has mild facial
dysmorphology that includes large ears. He also has excessive drooling.
He has scoliosis, gait disturbance, slender build, slender fingers, and
a history of extensive tremors. He was born to a non-consanguineous
family. He has a healthy and neurotypical younger male sibling. He
presents with global developmental delays, attention deficit disorder,
hyperactivity, impairment of fine and gross motor coordination,
generalized hypotonia, and temper tantrums. Anxiety, impulsivity, and
depression were also reported and he was diagnosed with anxiety and mood
arousal regulation disorder in 2007. Neuropsychological evaluation was
remarkable for poor attention span. Family history is noted for leukemia
in his paternal grandfather and possibly autism in his father's sister's
son. There is a history of autism spectrum disorder in both the paternal
and maternal side of the family.

The proband was born first in birth order from an unremarkable and
uncomplicated pregnancy, other than light spotting in the first
trimester. He was born at full term via normal, spontaneous vaginal
delivery with a birth weight of 8 lbs. 4 1/2 oz (95th percentile). There
were no perinatal complications. The proband's first febrile seizure was
noted at 11-12 months of age. The seizure was mild and lasted ten
minutes in duration. He then had multiple seizures after 17 months of
age. Recurrent seizures consist of blank stares, and repetitive jerks of
the head without dropping, that lasted a few seconds in duration. These
episodes were very frequent and may occur 10 to 20 times over a period
of thirty minutes. Ethosuximide was not effective in treating seizures
and was replaced with valproic acid with an improved response noted.

He had a history of no expressive language and an attention deficit
disorder. During an early clinic visit as a child, the boy was observed
to be social but nonverbal. He had absent speech but could communicate
using simple signing. EEG and CT scans were first conducted at one year
of age and were both unremarkable. Thirty-two years ago, chromosomal
studies were reported as unremarkable, although this would have been
karyotype only.

At 3 years, 3 months of age, referral to medical genetics was made. The
proband's height, weight, and head circumference were at the 85th, 75th,
and 45th percentile, respectively. The neurological exam showed
hyperactivity, impairment of fine and gross motor coordination, and
generalized hypotonia. Neuropsychological evaluation was remarkable for
poor attention span and learning and intellectual disability. His
expressive language was assessed as being less than an eight month level
and his receptive language was at 2 to 2 \selectlanguage{ngerman}½ year level. A Test of
Nonverbal Intelligence Test (TONI-4) was administered twice to assess
abstract reasoning and problem solving, of which he scored 85 and 119,
respectively on an index score of 100 and a standard deviation of 15. At
the same time, cytogenetic evaluation was performed to rule out Angelman
syndrome, (AS). Analyses indicated that the critical DNA region for AS
had not been deleted; although it was noted that additional DNA markers
were needed to completely rule out AS.

At four years of age, he had a weight, height, and head circumference of
50th, 90th, and 45th percentile, respectively. His weight percentile
dropped from 85\textsuperscript{th} to 50\textsuperscript{th}, and to
this day he is lean. He did not have expressive language and could only
say ``hi'' or ``bye.'' The subject was able to follow one and two-step
commands and had poor coordination. The proband was referred to a
psycholinguistic evaluation and was diagnosed with Seizure disorder and
Developmental Receptive and Expressive Language disorder. At six years
of age, EEG was indicative of diffuse cerebral dysfunction, and
consistent with a diagnosis of primary generalized epilepsy. He only
developed limited spoken language despite receiving nonverbal cognitive
scores in the average range of his age. Valproic acid was increased to
500 mg bid, from 125 mg bid and carnitine was recommended. By 10 years
of age, the proband's nonverbal mental age did not continue to maintain
the same rate of change as his physical age, dropping to an IQ of 68, as
measured by the Leiter-R. He also underwent back surgery that year for
correction of severe kyphosis.

The next follow-up psychiatric visit was when the subject was 17 years
of age. He was noted to be ambulatory with abnormal gait, dysarthric,
with a continuance of tremors and seizures. Due to his significant hand
tremors, he required assistance with his daily living routine. He did
not exhibit self-injurious behavior and psychosis was not observed.

The proband was seen again for neuropsychological evaluation at 21 years
of age. His general intelligence function was assessed with the Stanford
Binet Intelligence Scales, Fifth Edition. He obtained a Verbal IQ of 43
(\textless{}1st percentile), a Nonverbal IQ of~52 (\textless{}1st
percentile), and a combined IQ of 45 (\textless{}1st percentile). This
score placed him in the moderately delayed range of general intelligence
function. His adaptive behavior was also estimated with the Vineland
Adaptive Behavioral Scales, Second Edition, which placed him at an
approximate age equivalent of 3 years 7 months. His adaptive skills,
including communication, daily living skills, and socialization, were
hindered in part by delays in communication skills and significant
tremors.

In 2023, and at 31 years of age, he returned again to the George A.
Jervis Clinic at the New York Institute for Basic Research, Staten
Island, New York for an updated psychological and genetic evaluation.
The proband continued to have extensive tremors which affected his daily
functioning such as feeding himself. He also had choreoathetosis and
possible dyskinesias. Ataxia was not noted. At the visit, Fragile X
testing was reported as negative. Brain MRI was unattainable because of
the steel rods placed following kyphosis correction surgery. The
proband's lipid panel was obtained (\textbf{Table 1} ) and showed
abnormally elevated levels of total cholesterol, triglycerides, LDL
cholesterol, and low HDL cholesterol, but a normal BMI of 21.7
kg/m\textsuperscript{2}. In 2023, additional lab testing did not find
any abnormality with his oxysterol profile (see \textbf{Table 2}
).\textbf{Table S1} shows a comprehensive list of the current
medications of the proband.~Epilepsy is currently controlled with
clonazepam.

\textbf{Genomic Analyses}

A whole genome single nucleotide polymorphism (SNP) microarray was
performed as a trio on the subject, mother, and father. A \emph{de
novo}2.62 Mb interstitial deletion of 6q22.l\_q22.31 was detected, which
is interpreted as pathogenic, as seen in \textbf{Table 3} . This
interval includes nine OMIM genes (\emph{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 (\emph{BZW2, TSPAN13, AGR2, AGR3, AHR,
SNX13} ). At this time, no clinically established disorders have been
reported with duplication of this region.

\textbf{DI} SCUSSION

The \emph{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). \emph{NUS1}was
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 \emph{NUS1} and the
promoter of SLC35F1, which were important contributors to tremors and
epilepsy (Szafranski et al. 2015). Variants of \emph{NUS1} have also
been linked with ataxia (Den et al. 2019). In some less common
cases,\emph{NUS1} contributes to parkinsonism, scoliosis, gestational
diabetes mellitus, and psychosis (Den et al. 2019; Jiang et al. 2022;
Fraiman et al. 2021). \emph{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
\emph{NUS1}variants 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.

\emph{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
involve\emph{ASF1A} deletion have a variant length over 1kb involving
multiple genes, making it difficult to attribute the connection
between\emph{ASF1A} to the neurodevelopmental symptoms. \emph{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 \emph{NUS1} (Szafranski et al. 2015). Thus, the
precise contribution of this gene or its lack thereof could not be
determined. Similarly, \emph{GOPC} is a gene that encodes a Golgi
protein that could contribute to infertility (Bizkarguenaga et al.
2019). Variants in ClinVar included \emph{NUS1} and other genes, making
it difficult to determine its contribution. Finally, \emph{ROS1} , a
proto-oncogene that encodes for either a protein or differentiation
factor could contribute to tumor development (Drilon et al. 2021).
Additional variants with\emph{ROS1} deletion included \emph{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 a\emph{NUS1} mutation as opposed to the other OMIM
genes.

\textbf{METHODS}

\emph{Fragile X testing:}

Genomic DNA was isolated and CGG repeat primed PCR analysis was
performed to determine the fragile X CGG repeat size.

\emph{Chromosomal Microarray:~}

The SNP microarray analysis utilized the Cytoscan HD platform,
incorporating over 743,000 SNP probes and 1,953,000 NPCN probes, with a
median spacing of 0.88 kb. Genomic DNA from the provided sample type
underwent extraction and digestion with NSP1, followed by ligation to
NSP1 adaptors. PCR products were subsequently purified and quantified.
The purified DNA was fragmented, biotin-labeled, and then hybridized to
the Cytoscan HD GeneChip. Data analysis was conducted using the
Chromosome Analysis Suite, referencing the GRCh37/hg19 assembly. The
test's development and performance characteristics were established by
LabCorp. Microarray analyses were conducted for both the subject and
their parents.

\emph{Oxysterol Testing:}

Assay for oxysterols was performed at Mayo Clinic Laboratories (Test
ID\#OXYWB). This test was developed and its performance characteristics
determined by Mayo Clinic in a manner consistent with CLIA requirements.
It has not been cleared or approved by the US Food and Drug
Administration.

\emph{EEG Testing:~}

EEG was used to evaluate a seizure disorder and the subject is currently
treated with Depakote. The EEG examination was performed while the
subject was in three stages of awake, drowsy, and asleep, using the
10-20 system of electrode displacement. Photic stimulation included a
stepwise manner from 1-30 Hz.

\emph{General Intellectual Function and Adaptive Function:~}

General intellectual function was assessed with the Stanford Binet
Intelligence Scale, Fifth Edition. Adaptive function was estimated based
on the information the mother provided via phone using the Vineland
Adaptive Behavioral Scales, Second and Third Editions.

\emph{Psycholinguistic Evaluation:~}

Evaluation methods included direct observation, record review, videotape
analysis, parent interview, and the Vineland Adaptive Behavioral Scale,
Second Edition. Additional methods to evaluate early language
development included the sentence verification task and the Peabody
Picture Vocabulary Test. The parents were administered the Vineland
Adaptive Behavioral Scale. Unfortunately, the subject was not compliant
to participate in this test.

Test of Early Language Development-Second Edition is a standardized
psycholinguistic instrument which measures language ability between the
ages of newborn and eight years of age.~The Sentence Verification Task
evaluated comprehension of children with limited productive skills by
presenting sentences orally and asking for the judgment of the truth of
the sentence.~The Peabody Picture Vocabulary test is a standardized
psycholinguistic instrument which presents four pictures and asks the
child to identify one from the group.

\textbf{ADDITIONAL INFORMATION}

\textbf{Ethics Statement}

Subject consent was obtained for research and publication, with approval
of protocol \#7659 for the Principal Investigator: G.J.L., of the George
A. Jervis Clinic by the New York State Psychiatric Institute--- Columbia
University Department of Psychiatry Institutional Review Board.

\textbf{Acknowledgments}

We thank the subject and his family for their collaboration and
participation in this research. Additionally, we thank Dr. Marc
Patterson for providing assistance and comments for the manuscript.

\textbf{Author Contributions}

J.Y.H, D.H.I., R.A. all contributed to data analysis and preparing the
original draft. E.M., M.G. and K.A. assisted with data acquisition.
G.J.L. was responsible for project conception, data acquisition,
supervising, reviewing, and editing the manuscript.

\textbf{Funding}

Funding for this report was provided by the George A. Jervis Clinic of
the New York State Institute for Basic Research in Developmental
Disabilities (IBR), New York State Office for People with Developmental
Disabilities.

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\textbf{Table 1:} Lipid Panel\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& Value (High/Low) & Reference Range\tabularnewline
Cholesterol, Total & 252 (H) & \textless{}200 mg/dL\tabularnewline
HDL Cholesterol & 35 (L) & \textgreater{} OR= 40 mg/dL\tabularnewline
Triglycerides & 272 (H) & \textless{}150 mg/dL\tabularnewline
LDL Cholesterol & 172 (H) & \textless{}100 mg/dL\tabularnewline
CHOL/HDLC Ratio & 7.2 (H) & \textless{}5.0\tabularnewline
Non HDL Cholesterol & 217 (H) & \textless{}130 mg/dL\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2} : Oxysterols\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Oxysterols & Concentration (nmol/m) & Reference Value
(nmol/m)\tabularnewline
Cholestane-3\selectlanguage{greek}β,\selectlanguage{english}5a,\selectlanguage{english}6\selectlanguage{greek}β-\selectlanguage{english}triol & \textless{} 0.055 & [?] 0.070\tabularnewline
7-Ketocholesterol & \textless{} 0.038 & [?] 0.100\tabularnewline
Lyso-sphingomyelin & \textless{} 0.006 & [?] 0.100\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 3} : NUS1 Variant Finding\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\textbf{Gene} & \textbf{Chr} & \textbf{Position} & \textbf{HGVS DNA
Reference} & \textbf{HGVS Protein Reference} & \textbf{Variant Type} &
\textbf{Predicted effect} & \textbf{dbSNP/dbVar ID} &
\textbf{Genotype}\tabularnewline
NUS1 & 6 & 6q22.31 & NM\_138459.5:g.117344163\_119962769del &
NP\_612468.1 & Deletion & Haploinsufficiency & n/a &
heterozygous\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 4} : Description of Deleted OMIM Genes\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Genes\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Description\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Conditions\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Pathogenicity\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
VGLL2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Vestigial Like Family Member 2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Spindle Cell Rhabdomyosarcoma; Pleomorphic Rhabdomyosarcoma\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Unknown\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ROS1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ROS Proto-Oncogene 1, Receptor Tyrosine Kinase\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Susceptibility to lung Cancer\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Unknown\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
GOPC\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Golgi Associated PDZ And Coiled-Coil Motif Containing\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Spermatogenic Failure 9 and \emph{Acute Laryngitis}.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Unknown\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NUS1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
NUS1 dehydrodolichyl diphosphate synthase subunit\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Congenital Disorder of Glycosylation, Type Iaa, and autosomal dominant
type 55 intellectual disability with seizures\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Likely Pathogenic\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
CEP85L\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Centrosomal Protein 85 Like\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Lissencephaly 10 and \emph{Lissencephaly}.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Likely Pathogenic\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
PLN\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Phospholamban\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\emph{Cardiomyopathy, Dilated, 1P} and \emph{Cardiomyopathy, Familial
Hypertrophic, 18}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Likely Pathogenic\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
MCM9\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Minichromosome Maintenance 9 Homologous Recombination Repair
Factor\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\emph{Ovarian Dysgenesis 4} and \emph{Premature Ovarian Failure 1}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Likely Pathogenic\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ASF1A\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Anti-Silencing Function 1A Histone Chaperone\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\emph{Cataract 34, Multiple Types} and \emph{Alpha-Thalassemia}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Unknown\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
MAN1A1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Mannosidase Alpha Class 1A Member 1\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\emph{Congenital Disorder Of~} \emph{Glycosylation, Type I}Iu\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Unknown\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\selectlanguage{english}
\FloatBarrier
\end{document}

