European Journal of Medical Genetics

European Journal of Medical Genetics 62 (2019) 248–253
Contents lists available at ScienceDirect
European Journal of Medical Genetics

journal homepage: www.elsevier.com/locate/ejmg
A family with floppy neonates with severe respiratory insufficiency: A lethal T

phenotype of RFT1-CDG due to a novel mutation
Thangaraj Abiramalathaa,b, Gautham Arunachalc, Karthik Muthusamyd, Niranjan Thomasa,∗
a
Department of Neonatology, Christian Medical College, Vellore, India
b
Department of Neonatology, Sri Ramachandra Medical College and Research Institute, Chennai, India
c
Department of Clinical Genetics, Christian Medical College, Vellore, India
d
Department of Pediatric Neurology, Christian Medical College, Vellore, India
A R T I C LE I N FO A B S T R A C T
Keywords: Congenital disorders of glycosylation (CDG) are a rapidly expanding group of inborn errors of metabolism with
Congenital disorders of glycosylation around 100 types described so far. Because of the limited number of reported cases in each type except PMM2-
RFT1 CDG, the complete clinical picture of other types is not known. RFT1-CDG is a rare type, with ten cases reported
Floppy neonate in the literature. Our patient presented as a floppy neonate with severe respiratory insufficiency and ventilator
Respiratory insufficiency
dependence in the newborn period. He had fetal growth restriction, facial dysmorphism, high arched palate,
bilateral cryptorchidism, hypoplastic pons and cerebellum and probable hearing impairment. He succumbed to
the illness on day 24 of life. There was a similar history of two previous sibling deaths in the early neonatal
period due to respiratory insufficiency and history of multiple neonatal and infant deaths in the extended family.
Transferrin iso-electric focusing was normal. Clinical exome sequencing revealed a novel homozygous missense
mutation (c.1018 G > A) in RFT1 gene [NM_052859; c.1018G > A; p.G340S; ENST00000296292] and the
parents were heterozygous for the same (ClinVar SVC000778540). The pathogenic variants so far reported are
all missense variants affecting the luminal loops; whereas the variant in our case is in the trans-membrane helical
domain. A strong family history of neonatal deaths and similar presentations in the previous 2 siblings suggests
the homogenous phenotype of this mutation. Severe respiratory insuffiency and ventilator dependence shows the
lethality of the disease phenotype and incompatibility with survival beyond the neonatal period.
1. Introduction present in more than 80% of the cases (Freeze et al., 2015). Because of
the limited number of reported cases in each type except PMM2-CDG,
‘Floppy infant’ is a generic term that includes numerous differential the complete clinical picture of other types is not known (Peanne et al.,
diagnoses. Despite several established algorithms and guidelines, di- 2017, Schiff et al., 2017).
agnosis of the underlying etiology in a floppy baby is often difficult and Here we report a floppy neonate diagnosed with a rare type of CDG,
may remain elusive even after extensive work up. Birdi et al. reported RFT1-CDG (earlier nomenclature CDG, type1n) and describe a novel
that a definite diagnosis could be found in only 67% of the cases (Birdi mutation in the RFT1 gene. Clinical exome sequencing helped us arrive
et al., 2005). at the diagnosis.
Congenital disorders of glycosylation (CDG) are a rapidly expanding
group of inborn errors of metabolism (Scott et al., 2014, Francisco et al., 1.1. Case report
2018). Glycosylation of proteins and lipids is deficient, resulting in
defective and malfunctioning glycoproteins and glycolipids. Around The baby boy was born to a 28-year old fourth gravida mother with
100 different types of CDG have been described (Freeze et al., 2015). two previous neonatal deaths and one miscarriage. Her first child was a
The clinical phenotype of CDG is highly variable with some cases pre- girl, born at term gestation with a birth weight of 1500g. The baby had
senting with features of single organ involvement and others mimicking shortened long bones in the antenatal ultrasound and was suspected to
syndromes such as skeletal dysplasia, cutis laxa syndrome, or con- have skeletal dysplasia. She had perinatal asphyxia, required ventilator
genital muscle dystrophy (Funke et al., 2013). Neurological features are support from birth and died on day 5 of life. The second child was also a
∗
Corresponding author. Department of Neonatology, Christian Medical College, Vellore, 632004, Tamil Nadu, India.
E-mail address: niranjan@cmcvellore.ac.in (N. Thomas).
https://doi.org/10.1016/j.ejmg.2018.07.023
Received 9 November 2017; Received in revised form 3 July 2018; Accepted 28 July 2018
Available online 31 July 2018
1769-7212/ © 2018 Elsevier Masson SAS. All rights reserved.
Descargado para Venus Ramses Martínez de la Vega (ramsesvega06@outlook.com) en Sciences and Higher Education Institute of Tamaulipas de ClinicalKey.es por Elsevier en
noviembre 11, 2023. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.
T. Abiramalatha et al. European Journal of Medical Genetics 62 (2019) 248–253
Fig. 1. Three generation Pedigree chart.
term, girl baby with a birth weight of 1700g. She apparently cried at syndrome, ponto-cerebellar hypoplasia and brain stem/posterior fossa
birth, but became apneic at 30 min of life, given ventilator support and malformations. There was no myotonia or fatigability in the mother.
died on day 3 of life. There were no dysmorphism or external anomalies The infant's serum creatinine phosphokinase (CPK) was 181 U/L (re-
in either of the babies according to the parents. The parents were ference range: 87-725 U/L). His chest radiograph showed thin ribs, but
second degree consanguineous. There was also a history of multiple no eventeration of diaphragm. Echocardiogram and ultrasound ab-
neonatal and infant deaths in the family (Fig. 1). domen were normal. Serum acyl-carnitine profile and aminoacidogram
In the present pregnancy, there was no history of fetal hypokinesia by tandem mass spectrometry were normal. Magnetic resonance ima-
or polyhydramnios. Labor was induced at 34 weeks gestation for fetal ging (MRI) of the brain showed hypoplastic pons and cerebellum,
intra-uterine growth restriction and abnormal Doppler. Baby did not simplified gyral pattern involving both the cerebral hemispheres with
cry at birth and required resuscitation with positive pressure ventila- relative sparing of the parietal lobes; myelination was normal and there
tion. Since the respiratory efforts were persistently shallow, he was was no calcification or diffusion restriction (Fig. 2). Nerve conduction
intubated and ventilated. study was normal; repetitive nerve stimulation was tried, but was
The baby was a boy, with a birth weight of 1570g (< 3rd centile), technically difficult and could not be interpreted. Therapeutic challenge
length 40 cm (< 3rd centile) and head circumference 31 cm (between with neostigmine did not produce a consistent response. Histopathology
10th and 50th centile). He had high arched palate and bilateral cryp- including electron microscopy of the Quadriceps femoris muscle biopsy
torchidism. He had dysmorphic features such as triangular face, sparse was normal. Hearing screening by automated auditory brainstem re-
eyebrows, thick gums and malar flattening. There was no limb con- sponse (ABR) at 35 decibel was bilateral ‘refer’ and further evaluation
tracture. could not be completed.
The baby had no encephalopathy or seizures. Extra-ocular move- Targeted Clinical exome (SureSelect Focused Exome from Agilent
ments, pupillary reaction, facial grimace, palatal and tongue move- Genomics) sequencing of trio (proband and parents) was performed in
ments were normal. Muscle tone was reduced and deep tendon reflexes an attempt to get a final diagnosis. Interpretation of data was based on a
could not be elicited. Spontaneous movements were present though prior hypothesis of an autosomal recessive inheritance or an autosomal
reduced, with the best-observed power of at least 3/5 in all 4 limbs. dominant inheritance with reduced penetrance/expressivity. Careful
He had episodes of hypocarbia and hypercarbia while on the same screening for all the genes involved in such phenotypes discussed above
ventilator settings. On day 7 of life, he was extubated and could be in differential diagnoses section was performed. No significant variants
maintained on continuous positive airway pressure (CPAP) for 48 h, were found in these genes. However, there was no coverage for some
followed by room air for 12 h. However, he developed severe re- important genes of interest like CHRNA, CHRNB, END3, and ALG14, an
spiratory acidosis and needed to be re-ventilated. Further attempts at inherent limitation of the kit. Coverage for the rest of the genes of in-
weaning failed due to inadequate respiratory efforts and respiratory terest was complete.
acidosis. On day 24 of life, parents requested non-escalation of therapy Whole variant list from the original data was further screened for
after a failed weaning attempt, following which he succumbed to the variants with questionable significance. The variants were screened in
illness. the light of segregation pattern in parents compatible with our hy-
pothesis. A homozygous variant at position c.1018 G > A
[NM_052859; c.1018G > A; p.G340S; ENST00000296292 transcribed
1.2. Investigations and work up
from reverse strand; Genomic coordinate hg19 build chr3:53138053] in
exon 10 leading to an amino acid substitution Glycine to Serine
The differential diagnoses considered were congenital myasthenic
[p.G340S] was found in the RFT1 gene. The parents were heterozygous
syndrome, congenital muscular dystrophy, Spinal muscular atrophy
for the same variant. The variant has not been previously reported with
with respiratory distress (SMARD), congenital central hypoventilation
249
Fig. 2. MRI T1 axial image (A) shows simplification

of the gyral pattern with no obvious thickening of
the gyri. T1 sagittal image (B) and T2 axial (C)
shows hypoplasia of pons and cerebellum. Also note
the T1 and T2 myelination of posterior limb of in-
ternal capsule (PLIC) and deep cerebellar white
matter, which is normally expected for this age.
Table 1 the disease (we submitted for our case; ClinVar SVC000778540).
In silico prediction tools and the predictions. However it has a very low frequency in the general population, with
TOOLS PREDICTIONS
only 4 individuals in EXAC and 1 individual in 1000 genomes carrying
the allele in heterozygous form; never in homozygous state [dbSNP ID:
MUTATION TASTER Disease Causing rs568474177]. The variant is predicted deleterious/damaging/disease
POLYPHEN Probably Damaging [Score: 1.000] causing by various in silico prediction tools for all the protein coding
SIFT Damaging [Score: 0.00]
transcripts (Table 1). The native amino acid Glycine is highly conserved
PROVEAN Deleterious [Score: −5.39]
MUTATIONASSESSOR High Impact across species and is in one of the trans-membrane helical domain. The
SNAP Non Neutral [Score: +63 Accuracy: 80%] variant was validated by Sanger sequencing in the DNA of the proband
MUpro Decrease in Stability of Protein Structure and his parents (Fig. 3). DNA of other affected siblings and other af-
Delta G = −1.4111373
fected family members was not available, hence clear segregation
Fig. 3. RFT1 gene chromatogram.
250
Table 2
Clinical and Genetic profile of the reported RFT1 cases.
Publication Mutation Origin Age of Development Seizure Feeding Tone/DTR Visual Deafness Coagulation Dysmorphic Other clinical Outcome MRI
Presentation delay/ difficulty disorder features features
Intellectual
T. Abiramalatha et al.
disability
Haeuptle et al., Homozygous Caucasian Fetal/ + Refractory Severe Marked Decreased + Recurrent Antimongoloid Fetal growth Died at Atrophy of both
2008 mutation Newborn seizures, with hypotonia, VA, roving venous palpebral restriction, 4.3 years the cerebral
Imtiaz, 2000 c.199C > T myoclonus recurrent normal to brisk eye thrombosis fissures, pectus decreased fetal hemispheres
Clayton and (p.R67C) choking DTR, episodic movements, carinatum, movements, and the
Grunewald, arching of reduced amounts shortened long posterior fossa
2009 back and tonic of cartilage in bones, diarrhea, structures
posturing of the pinnae, small hepatomegaly,
limbs chest,
arthrogryposis
Vleugels et al., Homozygous Scottish Infancy Severe Refractory Severe Hypotonia Decreased + _ Micrognathia, Respiratory Died at 8 Cerebral
2009 mutation generalized VA short neck, small insufficiency months atrophy (at
c.199C > T seizures, nose, drooping autopsy)
(p.R67C) Infantile eyelids, valgus
spasms feet, adducted
thumbs.
Vleugels et al., Homozygous Italian Infancy Severe Refractory Severe, Hypotonia Nystagmus + Recurrent Inverted nipples – Alive at Progressive
2009 mutation Relapsing initially, later venous kyphoscoliosis 5.5 years cortical and
c.454A > G aspiration Spastic thrombosis, subcortical
(p.K152E) pneumonia tetraparesis Stroke atropy
Vleugels et al., Homozygous Algerian Infancy Severe + + Hypotonia, Poor vision, + NR Inverted nipples, Respiratory Alive at Normal
2009 mutation body spasm bilateral infiltrated ears, insufficiency 2.2 years
c.892G > A glaucoma short neck, chronic
251
(p.E298 K) retrognathism, infections of the
glossoptosis, respiratory
adducted tract.
thumbs, valgus
feet.
Jaeken et al., Homozygous Moroccan Newborn Severe + + Axial Erratic eye + Thrombophilia Small chin Retropulsion of ? Normal
2009 mutation hypotonia, movements, the head,
c.454A > G hypertonia of internal stridorous
(p.K152E) the finger strabismus inspiration,
flexors, brisk episodic apneas,
DTR Fetal growth
restriction
Jaeken et al., Compound Italian Newborn + Refractory Severe Severe NR + Venous Anteverted Respiratory ? Symmetrical
2009 heterozygous for hypotonia, thrombosis nostrils, insufficiency lesions of basal
2 mutations absent DTR, depressed and from birth ganglia, cortical
c.887T > A broad nasal atrophy, diffuse
(p.I296K) and bridge, small supratentorial
c.887T > G mouth, inverted white-matter
(p.I296R). nipples. hyperintensity,
unmyelinated
capsula interna
Ondruskova Compound Czech 21 years Severe + NR Axial Normal + Thrombophilia Mild Kyphoscoliosis, Alive Normal
et al., 2012 heterozygousfor hypotonia, dysmorphism short stature
two mutations mild spasticity,
c.1222A > G hyperreflexia,
(p.M408V) and ataxia
c.1325G > A
(p.R442Q).
Czech 19 years Severe NR Normal _ Thrombophilia Alive Normal
(continued on next page)
Table 2 (continued)
Publication Mutation Origin Age of Development Seizure Feeding Tone/DTR Visual Deafness Coagulation Dysmorphic Other clinical Outcome MRI
Presentation delay/ difficulty disorder features features
Intellectual
disability
T. Abiramalatha et al.
Ondruskova Compound Myoclonic Axial Mild

et al., 2012 heterozygous for seizures hypotonia, dysmorphism,
two mutations mild spasticity kyphoscoliosis
c.1222A > G with brisk
(p.M408V) and DTR, Ataxia
c.1325 G > A
(p.R442Q)
Aeby et al., 2016 Homozygous Moroccan Newborn Severe Refractory Severe Hypertonia, Convergent + NR NR Subcutaneous Died at 1 Normal
mutation brisk DTR, strabismus limb oedema year
c.454A > G adducted
(p.K152E) thumbs
Aeby et al., 2016 Compound Italian Newborn Severe Refractory + Hypertonia, Erratic eye + NR NR Irritability, Died at 2 Non-specific
heterozygous for brisk DTR, movements, wailing years lesions in the
two mutations retraction of convergent respiratory frontal
c.1325G > A the knees and strabismus insufficiency periventricular
(p.R442Q) and elbows, severe white matter
c.110G > T tetraparesis
(p.R37L)
Our case Homozygous Indian Newborn _ Nil NK Hypotonia, Eye + NK High arched Respiratory Died on Hypoplastic
mutation absent DTR movements palate, bilateral insufficiency day 24 pons and
c.1018 G > A normal, VA - cryptorchidism, Fetal growth of life cerebellum,
(p.G340S) NK triangular face, restriction simplified gyri
sparse eyebrows, pattern
252
thick gums and involving both
malar flattening the cerebral
hemispheres
Abbreviations: DTR - Deep tendon reflexes; NK - Not Known; NR - Not Reported; VA - Visual Acuity.
analysis was not possible. Further general screening for all the null confirmation. A strong family history of neonatal deaths and similar
variants picked by the next-generation sequencing (NGS) panel along presentations in the previous 2 siblings suggests the homogenous phe-
with their segregation pattern was performed and looked for any clin- notype of this mutation. Severe respiratory insuffiency and ventilator
ical relevance. Parting 2 compound heterozygous null variants in MYH8 dependence shows the lethality of the disease phenotype and in-
gene in cis-configuration, which are currently considered as variants of compatibility with survival beyond the neonatal period.
uncertain significance, none had any clinical correlation (Dia et al., To conclude, RFT1-CDG is a rare type of CDG that could present as a
2017). Collating the above findings, the variant c.1018 G > A was floppy infant with respiratory involvement. We have reported a novel
considered likely pathogenic. The parents were counseled about the mutation in the RFT1 gene, which proves to be lethal in the neonatal
25% chance of recurrence, the limited therapeutic options and the period.
possibility of prenatal diagnosis in the next pregnancy.
Conflicts of interest
2. Discussion
None.
RFT1-CDG is a rare type, caused by mutation in RFT1 gene located
in the short arm of chromosome 3. The gene product is a critical ac- Appendix A. Supplementary data
cessory that catalyzes the translocation of the intermediate metabolite
of the glycosylation pathway (Man5GlcNAc2-PP-dolichol) from cyto- Supplementary data related to this article can be found at https://
plasm to endoplasmic reticulum, which is important to facilitate further doi.org/10.1016/j.ejmg.2018.07.023.
steps in the pathway.
The first case of RFT1-CDG was reported in 2008 (Clayton and References
Grunewald, 2009, Haeuptle et al., 2008). Since then, 10 cases have
been reported (Vieugels et al., 2009, Jaeken et al., 2009, Ondruskova Aeby, A., Prigogine, C., Vilain, C., Malfilatre, G., Jaeken, J., Lederer, D., Bogaert, P.V.,
et al., 2012, Aeby et al., 2016). RFT1-CDG is a severe type, known to 2016. RFT1-congenital disorder of glycosylation (CDG) syndrome: a cause of early-
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2008, Clayton and Grunewald, 2009, Vieugels et al., 2009, Jaeken emphasis on cerebellar involvement. Semin. Neurol. 34, 357–366.
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Francisco, R., Pascoal, C., Marques-da-Silva, D., Morava, E., Gole, G.A., Coman, D.,
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the first case reported by Clayton et al. (Clayton and Grunewald, 2009, disorders of glycosylation (CDG): Quo vadis? Eur. J. Med. Genet. (17), 30494–30499.
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protein is yet unknown. This requires further functional studies for
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European Journal of Medical Genetics 62 (2019) 248–253

Contents lists available at ScienceDirect

European Journal of Medical Genetics

A family with ﬂoppy neonates with severe respiratory insuﬃciency: A lethal T

Fig. 1. Three generation Pedigree chart.

Fig. 2. MRI T1 axial image (A) shows simpliﬁcation

Fig. 3. RFT1 gene chromatogram.

Ondruskova Compound Myoclonic Axial Mild

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