Cerebro‐oculo‐facio‐skeletal syndrome caused by the homozygous pathogenic variant Gly47Arg in ERCC2

Abstract

DNA damage repair is a pivotal mechanism in life. The nucleotide excision repair pathway protects the cells against DNA damage and involves XPD, an ATP dependent helicase that is part of the multisubunit protein complex TFIIH. XPD is encoded by the excision repair cross‐complementation group 2 gene (ERCC2). Only three patients with cerebro‐oculo‐facio‐skeletal syndrome (COFS), caused by mutations in ERCC2, have been published so far. This report describes a boy with the homozygous amino acid change p.Gly47Arg in XPD. He presented with profound microcephaly, psychomotor retardation, failure to thrive, cutaneous photosensitivity, a bilateral hearing deficit and optic atrophy, thrombocytopenia, and recurrent episodes of pneumonia. We report the first homozygous occurrence of the pathogenic variant Gly47Arg in the ERCC2 gene. Occurring homozygous, this variant was associated with COFS syndrome, leading to early death of the patient at the age of 21 months.

Full text

CLINICAL REPORT
Cerebro-oculo-facio-skeletal syndrome caused by the
homozygous pathogenic variant Gly47Arg in ERCC2
Janine Reunert | Alijda van den Heuvel | Stephan Rust | Thorsten Marquardt
Universitätsklinikum Münster, Klinik für Kinder
und Jugendmedizin, Münster, Germany
Correspondence
Thorsten Marquardt, Klinik für Kinder und
Jugendmedizin, Albert-Schweitzer-Campus
1, Gebaeude A13, 48149 Münster, Germany.
Email: marquat@uni-muenster.de
Abstract
DNA damage repair is a pivotal mechanism in life. The nucleotide excision repair
pathway protects the cells against DNA damage and involves XPD, an ATP depen-
dent helicase that is part of the multisubunit protein complex TFIIH. XPD is encoded
by the excision repair cross-complementation group 2 gene (ERCC2). Only three
patients with cerebro-oculo-facio-skeletal syndrome (COFS), caused by mutations in
ERCC2, have been published so far. This report describes a boy with the homozygous
amino acid change p.Gly47Arg in XPD. He presented with profound microcephaly,
psychomotor retardation, failure to thrive, cutaneous photosensitivity, a bilateral
hearing deficit and optic atrophy, thrombocytopenia, and recurrent episodes of pneu-
monia. We report the first homozygous occurrence of the pathogenic variant
Gly47Arg in the ERCC2 gene. Occurring homozygous, this variant was associated
with COFS syndrome, leading to early death of the patient at the age of 21 months.
KEYWORDS
COFS, DNA damage repair, ERCC2, XPD
1|INTRODUCTION
In order to preserve DNA fidelity, eukaryotic cells have developed vari-
ous DNA repair pathways. The nucleotide excision repair (NER) pathway
removes bulky adducts starting with a damage recognition step followed
by opening of the double stranded DNA and adduct removal, requiring
the interaction of specialized protein complexes (Spivak, 2015).
TFIIH is a multisubunit protein complex that is involved in NER as
well as in regular transcription (Compe & Egly, 2012; Oksenych &
Coin, 2010). The TFIIH complex consists of a core-complex including
the proteins XPB, p62, p52, p44, p34, trichothiodystrophy (TTD)-A
and XPD, and the CAK module comprised of CDK7, cyclin H, and
MAT1; core complex and CAK module are thought to be linked by the
XPD protein (Oksenych & Coin, 2010).
Excision repair cross-complementation group 2 gene (ERCC2), the cod-
inggeneforXPD,islocatedonchromosome 19q13.3, has 23 exons and
produces a protein of 761 amino acids with a molecular weight of
86.9 kDa. Variants in ERCC2 can lead to different autosomal recessive DNA
repair disorders including xeroderma pigmentosum (XP), TTD, Cockayne
syndrome (CS), and a severe form of CS known as cerebro-oculo-facio-
skeletal syndrome (COFS). The clinical spectrum ranges from mild to severe
including early death (Faghri, Tamura, Kraemer, & DiGiovanna, 2008; Fassihi
et al., 2016; Suzumura & Arisaka, 2010; Wilson et al., 2016).
We report on a patient with the homozygous Gly47Arg amino
acid change in the ERCC2 gene (XPD), leading to COFS syndrome and
early death at the age of 21 months. He is the first published homozy-
gous Gly47Arg patient and the fourth patient diagnosed with COFS
syndrome due to variants in the XPD gene.
2|MATERIALS AND METHODS
EDTA blood samples were obtained from the patient and his parents
after informed consent. Exome sequencing as trio analysis of the DNA
Received: 2 July 2020 Revised: 9 December 2020 Accepted: 12 December 2020
DOI: 10.1002/ajmg.a.62048
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.
Am J Med Genet. 2020;1–7. wileyonlinelibrary.com/journal/ajmga 1

of the patient and his parents was performed as described previously
(Park et al., 2019). Synonymous variants and variants in the UTR
region were excluded. All variants with a minor allele frequency of
>2% were also excluded and remaining variants were first compared
with an in-house database of >100 exomes and pathogenicity was
afterward rated using the prediction tool MutationTaster (Schwarz,
Cooper, Schuelke, & Seelow, 2014). Only variants that occurred less
than five times in our in-house database and were predicted to be
“disease causing”by MutationTaster, were considered further. Vari-
ants in the candidate list were analyzed and interpreted using
FIGURE 1 The patient at the age of 10 and 14 months. He presented with bilateral enophthalmia with nystagmus, unilateral cataract,
micrognathia, microcephaly, a prominent nasal bridge, and large ear pinna with deep set ears. Flexure contractures of knees, hips, toes and elbows
are evident and his hands were fisted. (a) Development of head circumference, length and weight showing a progressive microcephaly and height
and weight partially more than 3 SDs below mean (b)
2REUNERT ET AL.

Genedistiller (Seelow, Schwarz, & Schuelke, 2008), OMIM and publi-
cation data on PubMed.
3|RESULTS
3.1 |Clinical report
The second child of healthy consanguineous parents of Syrian origin
(second degree cousins) was born spontaneously after 41 weeks of
pregnancy. Two early miscarriages preceded this pregnancy. There
were no immediate postnatal concerns. Birth weight was 2.77 kg (Z-
score = −1.25), length 50 cm (Z-score = +0.06) and occipitofrontal cir-
cumference 32 cm (Z-score = −1.94) (see Figure 1b). Besides his
microcephaly, a limitation of abduction of the hips and cryptorchidism
were noted and he failed the neonatal otoacoustic emissions screen-
ing. Brain-stem-evoked-response audiometry confirmed bilateral sen-
sorineural hearing loss. In the following weeks, severe failure to
thrive, nystagmus, axial muscular hypotonia with increased muscle
tone, and flexion pattern in the limbs and light sensitivity of the skin
were noted. At 2 months of age, the boy was hospitalized due to
feeding difficulties and failure to thrive. A few months later, a cyto-
megalovirus (CMV) infection was diagnosed with elevation of serum
transaminases (AST 122 U/L [<80], ALT 144 U/L [<65]) and he was
referred to our hospital.
At the age of 6 months, he presented with microcephaly (see
Figure 1), muscle hypotonia, profound failure to thrive, and signifi-
cantly delayed psychomotor development; reddened dry and scaly
skin in sun-exposed areas and a horizontal nystagmus were noted. All
his life, he never learned to roll or sit independently. In extensive
blood examinations, a hypereosinophilia was noted and confirmed in
several independent blood samples. Metabolic screening for congeni-
tal disorders of glycosylation and organic acids was normal. No argu-
ments for hematological (thrombocyte count normal), oncologic or
immunologic diseases were found. CMV-PCR on neonatal dry blood
spot was negative, ultrasound showed no signs suspicious of congeni-
tal CMV infection either. MRI showed brain atrophy, a well formed
but thin corpus callosum and megacisterna magna; myelination and
migration seemed age appropriate. Ultrasound of the abdomen
showed no organ enlargement or lesions. Ophthalmologic evaluation
found bilateral optic atrophy and posterior polar cataract of the right
eye. CMV infection was excluded as explanation for his clinical syn-
drome and genetic investigations were initiated.
At the age of 10-month, application of a percutaneous endo-
scopic gastrostomy tube was necessary due to persistent feeding
problems with vomiting. Eosinophilia improved and body weight
increased (see Figure 1b), although bilious vomiting persisted. Recur-
rent episodes of pneumonia required frequent hospitalization includ-
ing intubation and ventilation once.
Figure 1a shows the boy at the age of 10 and 14 months. He had
bilateral enophthalmia with nystagmus, unilateral cataract,
micrognathia, microcephaly, a prominent nasal bridge and large ear
pinna with deep set ears. Flexure contractures of knees, hips, toes and
elbows are evident and his hands were fisted. His skin appeared to be
dry, scaly, and photosensitive. The parents recall skin reddening and
irritations in sun-exposed areas since birth with blister forming.
Besides mild facial freckling, no abnormal skin pigmentation was
noted at that time.
From the age of 14 months, a persistent and at times severe
thrombocytopenia (min. 11,000/μl [206–445 k/μl] see Figure 2) was
diagnosed with two relevant bleeding episodes. Platelet transfusions
showed no lasting improvement. Differential diagnosis raised suspi-
cion of an inefficient megakaryopoiesis, but at the same time, multiple
solid lesions in liver, spleen and kidney were found. These lesions
were never fully explained. Tumor markers were not elevated and
viral screening was negative. As they were very stable and no growth
was noticed over time, an infectious or tumorous origin is unlikely. As
he needed a bilateral orchiectomy (for cryptorchidism) at the age of
16 months, a liver biopsy was done at the same time to better define
these lesions. Pathology of the liver sample showed a mild
steatohepatitis with a beginning fibrosis and an increased number of
heterolysosomes.
At 18 months of age, predominant clinical symptoms were micro-
cephaly, severe psychomotor developmental retardation (develop-
mental age 8 weeks), failure to thrive, increased muscle tone with
contractures of hips and knees, visual and hearing impairment, photo-
sensitivity and numerous and increasing skin pigmentation spots, an
incomplete set of primary teeth, thrombocytopenia and recurrent
pneumonia. He died at the age of 21 months due to another pneumo-
nia with respiratory failure.
3.2 |Mutation analysis
The patient was found to be homozygous for the previously reported
pathogenic variant c.139G > A, p.(Gly47Arg) (NC_000019.9:
g.45872372C > T; GRCh37) in the ERCC2 gene (Gene ID: 2068). Addi-
tionally to MutationTaster (score 0.999999999999247), the Gly47Arg
amino acid change is also predicted to be disease causing by the in silico
programs Provean and Polyphen2 (Adzhubei et al., 2010; Choi &
Chan, 2015); CADD score is 29.4 (Rentzsch, Witten, Cooper,
Shendure, & Kircher, 2019). The variant has been reported in compound
heterozygosity with different defective alleles and different diseases
(Cleaver, Thompson, Richardson, & States, 1999; Fujimoto et al., 2005;
Horibata et al., 2015; Kondo et al., 2016; Taylor et al., 1997; Theron
et al., 2005; Zhang et al., 2017). Both parents are heterozygote carriers
and not affected by the disease.
The number of de novo variants was comparable to other in-house
exomes. There were no de novo variants in known disease genes.
4|DISCUSSION
The XPD protein belongs to a highly conserved superfamily of ATP-
dependent helicases (SF2), which are built by seven helicase motifs,
walker motif I, Ia, II, III, IV, V, and VI (Bienstock, Skorvaga, Mandavilli, &
REUNERT ET AL.3

van Houten, 2003; Gorbalenya & Koonin, 1993). XPB and XPD have
30>5
0and 50>3
0translocation polarity, respectively. It has been
suggested earlier that these helicases jointly open the ds-DNA helix at
opposite sides of the lesion (Schaeffer et al., 1994). However, they
have different roles in transcription and in the NER pathway. Whereas
ATPase activity of XPB is required for DNA opening in both pro-
cesses, the helicase activity is less pronounced in NER. In contrast to
XPB, the helicase activity of XPD is pivotal in NER, but less active in
transcription (Coin, Oksenych, & Egly, 2007; Dvir, Conaway, &
Conaway, 1997; Guzder et al., 1994; Richards, Cubeddu, Roberts,
Liu, & White, 2008). Helicase activity of XPD has been shown to be
regulated through interaction between the C-terminal end of XPD
and the TFIIH subunit p44 (Coin et al., 1998). Most known mutations
in ERCC2 are located in the C-terminal region and affect p44 interac-
tion (Coin et al., 1998; Dubaele et al., 2003). The Gly47Arg amino acid
change is located in the N-terminus in motif I (AA 35–51), required for
ATP binding and hydrolysis to fuel helicase activity. Gly47Arg abol-
ishes these activities completely (Dubaele et al., 2003), however it
does not destroy the TFIIH complex. The amount of TFIIH complex
containing the Gly47Arg variant is reduced as well as basal transcrip-
tion (Dubaele et al., 2003). In our Gly47Arg homozygous patient, we
observed a phenotype that is largely overlapping with the severe phe-
notypes of the ERCC2-associated disease spectrum.
COFS is usually caused by mutations in the XPG and CSB gene.
Only three patients with COFS syndrome caused by mutations in
the ERCC2 gene have been published so far (Graham et al., 2001;
Horibata et al., 2015), leading to death in early childhood. The
patient described by Graham et al. carried the compound heterozy-
gous amino acid changes Arg616Trp/Asp681Asn and died at the age
of 3 1/2 years (Graham et al., 2001). COFS-05-135 (Ile619del/
Arg666Trp) died at the age of 12 months due to respiratory insuffi-
ciency and COFS-Chiba1 (Gly47Arg/Ile619del) died from pneumo-
nia at the age of 5 months(Horibata et al., 2015). Horibata et al.
showed that Ile619del is functionally null and assumed that single
expression of Gly47Arg or Arg666Trp was the disease defining
cause (Horibata et al., 2015). These findings are in accordance with
the severe phenotype of our patient who solely expresses a protein
with the Gly47Arg substitution. Gly47Arg has been published in
patients with a compound heterozygous genotype (Cleaver
et al., 1999; Fujimoto et al., 2005; Horibata et al., 2015; Kondo
et al., 2016; Taylor et al., 1997; Theron et al., 2005; Zhang
et al., 2017). Of all Gly47Arg compound heterozygotes, one was
assessed as XP-D, three as XP-D/CS (mild to severe) and two as
COFS, including our patient (see Table 1). As most of the XPD
patients carry compound heterozygous variants, a prediction of
genotype–phenotype correlations is difficult.
A clear distinction between CS and COFS is difficult as symp-
toms are overlapping (Laugel et al., 2008; Natale, 2011; Suzumura &
Arisaka, 2010). Also in the literature, the classification is not consis-
tent and a few cases that were previously reported as CS, have
been proposed later by others to suffer from COFS as they fulfill
the diagnostic criteria (Laugel et al., 2008; Natale, 2011). Our
patient was born with microcephaly, hip contractures, severe eye,
and ear involvement, cryptorchidism and had feeding difficulties
from the beginning. These findings together with an extremely
severe psychomotor retardation and recurrent infections led to
early death at the age of 21 months. Regarding his clinical appear-
ance and severe progress, we would rather define this as COFS
instead of severe CS. Recurrent episodes of pneumonia occurred in
our patient and also led to death at age < 30 months in approxi-
mately 80% of COFS patients (Graham et al., 2001). Thrombocyto-
penia, which was persistent and clinically relevant in our patient,
has been present in at least two other patients with Gly47Arg (see
Table 1). These patients have been diagnosed with XP-D/CS. The
frequent occurrence of thrombocytopenia suggests that it is a con-
sequence of the ERCC2 defect.
FIGURE 2 Thrombocyte counts of our patient showing persistent and at times severe thrombocytopenia (min. 11,000/μl) starting at the age
of 14 months
4REUNERT ET AL.

TABLE 1 Overview of known patients carrying the pathogenic variant NP_000391.1:p.Gly47Arg in ERCC2 (Gene ID: 2068)
Patient XP1NE XP1JI COFS-Chiba1
Patient in Kondo
et al. (2016)
Patient 4 in Zhang
et al. (2017) Patient in this study
First allele Gly47Arg Gly47Arg Gly47Arg Gly47Arg Gly47Arg Gly47Arg
Second allele Leu461Val + del
716–730
Unknown Ile619del Arg616Gly Ile595Ser Gly47Arg
Age Deceased at 43 years
due to sepsis
Deceased at 28 months due to severe
liver dysfunction
Deceased <1 year due to
pneumonia
Deceased at
23 months due to
renal failure
10 years Deceased at 21 months due to
respiratory failure
Diagnosis XP-D, XP-D/CS XP-D/CS COFS XP-D/CS XP-D COFS
Gender Female Male Male Male Male Male
Intrauterine growth
retardation
+ Birth weight
2,325 g
−+ + Ns +
Microcephaly + + + + ns +
Micrognathia ns ns + ns ns +
Failure to thrive + + + + Mild growth
retardation
+
Flexion contracture ns ns + ns ns +
Thrombocytopenia + + ns ns ns +
Neoplasm of the skin −Squamous cell carcinoma ns ns −−
Hearing impairment + + ns ns ns +
Cutaneous
photosensitivity
++ + +++
Cryptorchidism na + Impalpable testes ns + ns +
Abnormality of the
eye
−Mild cataracts, atypical retinal
pigmentary degeneration, bilateral
optic atrophy
Microphthalmia Microphthalmia,
retinal atrophy,
hypoplasia of
macula
−Optic atrophy, posterior polar cataract
of the right eye
Abnormality of the
nervous system
Unsteady gait,
dysarthria
ns Infantile spasm Nystagmus, spastic
quadriplegia,
uncontrolled head
−Nystagmus, uncontrolled head, severe
developmental impairment
(psychomotor developmental
maximal age reached was 12 weeks)
Imaging abnormality
(MRI/CT)
Several skeletal
abnormalities,
cerebral and
cerebellar sulci,
ventricular
enlargement, low-
density cerebellar
vermis
Dilatation of the lateral and fourth
ventricles, bilateral basal ganglia
calcification, hypoplasia of the brain
stem and cerebellar vermis
ns Bilateral cortical
calcifications, brain
atrophy
ns Brain atrophy, a well formed but thin
corpus callosum and megacisterna
magna
(Continues)
REUNERT ET AL.5

It should be noted, that the involvement of XPD in DNA repair of
UV-induced lesions does primarily explain the XP-phenotype, that is,
photosensitivity, and as such of course is mainly restricted to light
exposed areas of the body. Therefore, we suggest that other pheno-
types in CS, TTD, and COFS are likely due to effects on the whole
TFIIH complex in transcription. It has been shown that a reduced basal
transcription due to TFIIH-defects is associated with TTD (Dubaele
et al., 2003). The TFIIH may also affect transcription of specific groups
of genes by interaction with further transcription factors. For exam-
ple, it has been shown, that ERCC2-mutations may prevent TFIIH-
dependent transactivation by nuclear receptors (Keriel, Stary, Sarasin,
Rochette-Egly, & Egly, 2002). With the XPD-Gly47Arg-variant up to
now, it has been explicitly shown for one artificial template that tran-
scription to mRNA was reduced to 37% of wild type (Dubaele
et al., 2003). It may be expected, that there is some range of differen-
tial expression that finally may contribute to the observed CS and
COFS phenotypes. Unfortunately, our patient died suddenly and no
cells for such expression analyses were left. Future XPD/CS/COFS
cases should be analyzed for transcriptome changes to get more
insight into the pathophysiology of CS/COFS.
In conclusion, we report on the first patient with the homozygous
pathogenic variant Gly47Arg in the ERCC2 gene. In compound hetero-
zygous status, this variant is thought to cause XP, XP-D/CS, and
COFS syndrome dependent on the variant located on the second
allele. Occurring homozygous, this pathogenic variant leads to severe
COFS syndrome and early death.
ACKNOWLEDGMENT
The authors thank the patients' family for their support.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
ORCID
Thorsten Marquardt https://orcid.org/0000-0002-9982-2981
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How to cite this article: Reunert J, van den Heuvel A, Rust S,
Marquardt T. Cerebro-oculo-facio-skeletal syndrome caused
by the homozygous pathogenic variant Gly47Arg in ERCC2.
Am J Med Genet Part A. 2020;1–7. https://doi.org/10.1002/
ajmg.a.62048
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