European Journal of Medical Genetics xxx (xxxx) xxxx

Contents lists available at ScienceDirect

European Journal of Medical Genetics

journal homepage: www.elsevier.com/locate/ejmg

Expanding the phenotypic spectrum of Mabry Syndrome with novel PIGO

gene variants associated with hyperphosphatasia, intractable epilepsy, and
complex gastrointestinal and urogenital malformations
Alexander M. Holtza, Amanda W. Harringtonb, Erin R. McNamarac, Agnieszka Kieliand,
Janet S. Soula,d, Mayra Martinez-Ojedaa, Philip T. Levya,∗
a
Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
b
Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
c
Department of Urology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
d
Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA

ARTICLE INFO ABSTRACT

Keywords: Mabry syndrome is a glycophosphatidylinositol (GPI) deficiency characterized by intellectual disability, dis-
Mabry syndrome tinctive facial features, intractable seizures, and hyperphosphatasia. We expand the phenotypic spectrum of
PIGO inherited GPI deficiencies with novel bi-allelic phosphatidylinositol glycan anchor biosynthesis class O (PIGO)
Epilepsy variants in a neonate who presented with intractable epilepsy and complex gastrointestinal and urogenital
Glycophosphatidylinositol
malformations.
VACTERL
Anal atresia
Esophageal atresia
GPI anchor

1. Introduction 2. Clinical report

Glycophosphatidylinositol (GPI) is a glycolipid anchor that tethers
proteins to the cell surface and regulates their trafficking into mem-
brane subdomains (Manea, 2018). GPI-anchored proteins play critical
roles to modulate cell signaling during embryogenesis (Zurzolo and
Simons, 2016). Mutations to the GPI biosynthetic pathway are re-
sponsible for Mabry syndrome, a condition characterized by hyper-
phosphatasia, anorectal anomalies, distinctive facial features, nail hy-
poplasia, treatment refractory seizures, developmental delay, and
intellectual disability (Tanigawa et al., 2017). The objective of this
report is to describe a case of a neonate with novel compound hetero-
zygous variants in the phosphatidylinositol glycan anchor biosynthesis
class O (PIGO) gene, who presented with complex gastrointestinal and
urogenital abnormalities, respiratory failure, and intractable epilepsy.
In addition, we review the available literature describing PIGO asso-
ciated Mabry syndrome to expand the phenotypic spectrum of inherited
glycophosphatidylinositol (GPI) deficiencies.
Our patient was a female infant born by normal spontaneous vaginal
delivery at 37 weeks and 6 days gestation to a 24 year-old gravida 4,
para 2022 mother. The prenatal course was complicated by bilateral
hydronephrosis and an irregular heart rate. APGARs were 7 and 7 at 1
and 5 min, respectively. The infant's birth weight was 3195g (Z-score
0). Physical exam in the delivery room was notable for an imperforate
anus. Attempts to pass an orogastric tube failed, a replogle was placed,
and subsequent chest radiogram demonstrated an esophageal pouch
and diagnosis of esophageal atresia. The infant developed respiratory
distress and hypoxemia requiring supplemental oxygen and was ad-
mitted to the neonatal intensive care unit.
Several dysmorphisms were noted on physical exam, including mi-
crocephaly, upslanted palpebral fissures, epicanthal folds, normoset
ears with thickened helices, downturned corners of the mouth with a
tented upper lip, microretrognathia, brachydactyly, and nail hypoplasia
(Fig. 1A–F). Several additional congenital anomalies were promptly
discovered consistent with VACTERL association (Vertebral defects,

Abbreviations: GPI, Glycophosphatidylinositol; PIGO, Phosphatidylinositol glycan anchor biosynthesis class O; VACTERL, Vertebral defects, anal atresia, cardiac
defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities
∗
Corresponding author. Division of Newborn Medicine, Boston Children's Hospital, 300 Longwood Avenue | Hunnewell 436, Boston, MA, 02115, USA.
E-mail address: philip.levy@childrens.harvard.edu (P.T. Levy).

https://doi.org/10.1016/j.ejmg.2019.103802
Received 13 June 2019; Received in revised form 5 October 2019; Accepted 30 October 2019
1769-7212/ © 2019 Published by Elsevier Masson SAS.

Please cite this article as: Alexander M. Holtz, et al., European Journal of Medical Genetics, https://doi.org/10.1016/j.ejmg.2019.103802
A.M. Holtz, et al.
Anal atresia, Cardiac defects, Tracheo-Esophageal fistula, Renal
anomalies, and Limb abnormalities). An echocardiogram revealed a
small patent foramen ovale and a small ductus arteriosus. There were
no significant vertebral or limb anomalies noted; however, skeletal
survey identified an absent distal phalangeal ossification center of the
left 5th finger with a tiny one on the right (Fig. 1E, arrow), in addition
to a lack of ossification of the distal phalanges of the 2nd through 5th
toes (Fig. 1F, arrows).
A primary repair of the esophageal atresia with ligation of the tra-
chea-esophageal fistula was performed on day 2 of age. Following this
initial intervention, she required intermittent intubation in the setting
of multiple procedures and diagnostic studies. She was ultimately ex-
tubated and maintained on non-invasive respiratory support, but over
the course of three months she developed an esophageal stricture and
severe tracheobronchomalacia with intermittent desaturations re-
quiring suctioning, position changes, and stimulation. She ultimately
required continuous BiPAP support to maintain normoxemia and nor-
mocarbia.
Several anomalies were noted throughout the genitourinary system
based on clinical examination, abdominal ultrasound, and voiding cy-
stourethrogram: duplicated vagina and uterus with normal appearing
cervices, bilateral echogenic kidneys with dilated pelvices and calyces,
peripheral renal cysts, tortuous and dilated ureters, marked bilateral
hydroureteronephrosis and a recto-vestibular fistula with imperforate
anus. On VCUG there was no evidence of vesicoureteral reflux. A cy-
stoscopy identified a normal, yet elongated urethra and an opening
located posteriorly and distal to the ureteric ridge that could not be
probed. Neither ureteral orifice could be identified. Her course was
complicated by Klebsiella pneumoniae urosepsis with the development of
massive left hydroureteronephrosis with pyonephrosis requiring inser-
tion of a percutaneous nephrostomy tube.
During the early neonatal period at 3 weeks of age, she underwent
exploratory laparotomy for concerns of a small colon identified on
contrast study and inability to adequately empty through the dilated
rectovestibular fistula. An open gastrostomy-tube was placed with
creation of a colostomy and mucous fistula. She had significant feeding
intolerance requiring prolonged periods of parenteral nutrition. She
developed parenteral nutrition associated cholestasis with a peak direct
bilirubin of 8.0 mg/dL and a mild liver transaminase elevation.
Diagnostic workup included an unremarkable liver ultrasound and
negative infectious studies (normal CMV titers, negative enterovirus,
2
European Journal of Medical Genetics xxx (xxxx) xxxx
Fig. 1. Dysmorphology associated with compound
heterozygous PIGO variants. (A) Image at 10
weeks of age demonstrates up-slanting palpebral
fissures, epicanthal folds, downturned corners of
the mouth, a tented upper lip, and micro-
retrognathia. (B) Profile reveals a large dys-
morphic ear. (C) Images of the hand show distal
digit hypoplasia and nail dysplasia. Note similar
features in the foot (D), arrow denotes absent nail.
(E) XR of the hand, arrow denotes an absent distal
phalangeal ossification center of 5th finger, (F), XR
of the foot, arrows show lack of ossification of the
distal phalanges of 2nd through 5th toes.
HHV6, and EBV PCR). Metabolic workup was also non-diagnostic with
a normal newborn screen, plasma amino acids, urine organic acids,
urine bile acids, and very long chain fatty acids. Alpha-1 antitrypsin
phenotyping was normal. The patient's direct hyperbilirubinemia re-
solved after discontinuing parental nutrition and advancing enteral
feeds. However, her alkaline phosphatase levels were > 1500 U/L and
there was evidence of mild osteopenia on radiography studies.
Her initial chromosomal microarray and cholestasis sequencing panel
were normal. Trio whole genome sequencing revealed compound het-
erozygous variants in the PIGO gene that were inherited in trans, including
one variant of undetermined significance [NM_032634.4:c.1352T > G; p.
(Met451Arg), ClinVar ID 373818] and one likely pathogenic frameshift
variant [NM_032634.4:c.1392delinsGA; p.(Ile464Mfs*42); ClinVar ID
623646]. Additional findings included a heterozygous variant of un-
determined significance in the KRAS gene [NM_004985.4:c.460G > T; p.
(Asp154Tyr)] that was maternally inherited. A paternally inherited het-
erozygous variant of undetermined significance in the MFN2 gene
[NM_014874.3:c.748C > T; p.(Arg250Trp); ClinVar ID 543219] was also
found. Given the high degree of overlap with other children with bi-allelic
PIGO variants and the lack of significant parental medical history related
to the KRAS and MFN2 variants, a diagnosis of Mabry syndrome, also
known as hyperphosphatasia and mental retardation syndrome (PMHRS),
was made.
At two months of age, the patient developed episodes of seizure-like
activity with insuppressible movements of her upper extremities and
trunk; however, EEG reportedly did not show an electrographic seizure
correlate. Her EEG background was initially very abnormal, with gen-
eralized background slowing, and a burst suppression pattern with
prolonged inter-burst interval consistent with severe diffuse cerebral
dysfunction. She subsequently developed seizures characterized by
tonic posturing of her shoulders and arms with intermittent arm flexion,
lip smacking, hypoxemia with visible perioral/facial cyanosis. A sub-
sequent EEG at 4 months of age confirmed accompanying electro-
graphic seizure activity with a generalized spike and slow wave fol-
lowed by electrodecrement, then runs of rhythmic focal centroparietal
spikes lasting ~30–60 s. Her EEG background pattern continued to
show a severe diffuse encephalopathy with frequent periods of dis-
continuity lasting up to 20 s, no anterior-posterior gradient or posterior
dominant rhythm, a lack of state changes, and frequent multifocal
sharps, spike waves and polyspikes. Clinical and subclinical seizures
occurred from 4 to 5 and even up to 27 times per hour. Seizures
A.M. Holtz, et al.
persisted despite treatment with several antiepileptic medications with
a final regimen of levetiracetam 50 mg/kg/day, lacosamide 10 mg/kg/
day, and phenobarbital 5 mg/kg/day. No EEG changes were observed
after a 100 mg IV bolus of pyridoxine. Brain MRI scans at about 4 and
4.5 months of age showed similar findings of symmetric decreased
diffusivity and T2 prolongation in the medial globus pallidi and tha-
lami, red nucleus, substantia nigra, dorsal pons and cerebellar dentate
nuclei, and middle cerebellar peduncles. She had a thin corpus cal-
losum, hypoplastic vermis, optic nerves and chiasm, prominent sulci
and CSF spaces and a frontotemporal subdural fluid collection. Her
neurologic exam at that age was notable for borderline microcephaly,
minimal spontaneous waking and eye opening, occasional blink to light
but no visual fixation, significant proximal > distal weakness and
hypotonia, distal appendicular spasticity, and frequent nonpurposeful
movements of her face and limbs when awake. Auditory brain stem
response testing revealed only wave I with no other repeatable wave-
forms.
Further airway interventions to address the severe tracheo-
bronchomalacia were ultimately not pursued given her critical illness,
intractable seizures, and expected long-term neurologic prognosis. The
patient ultimately stabilized and was discharge home. Metrics at last
examination prior to transfer at 5-months of age were weight 6.71 kg
(Z-score −0.1), length 59 cm (Z-score −1.9), and head circumference
39 cm (Z-score −1.68). At 9 months of age, she developed respiratory
failure requiring intubation due to rhinovirus infection and Klebsiella
urosepsis leading to shock with multi-organ dysfunction. Her family
made the compassionate decision to defer further extreme measure and
she died after withdrawing supportive measures.
3. Discussion
Glycophosphatidylinositol (GPI) is a glycolipid that anchors soluble
proteins to the outer leaflet of the plasma membrane. There are over
150 GPI-anchored proteins in the mammalian genome that play critical
roles in embryogenesis, cell signaling, adhesion/migration, metabolism,
the immune response, and many other cellular processes (Manea,
2018). GPI-anchored proteins are preferentially sorted into sphingo-
lipid- and cholesterol-containing membrane microdomains, or rafts,
and are targeted to the apical surface of polarized cells (Zurzolo and
Simons, 2016). These proteins can also be released from the cell surface
via phospholipase-mediate cleavage of the GPI anchor (Fujihara and
Ikawa, 2016). The biosynthesis, protein attachment, maturation, and
subcellular trafficking of GPI-anchored proteins involves more than 30
genes, many of which have been implicated in human disease (Bellai-
Dussault et al., 2018).
There are over 200 patients described in the literature with defects
in GPI-anchored protein biosynthesis, known as inherited GPI defi-
ciencies. Patients with inherited GPI deficiencies present on a broad
phenotypic spectrum with both overlapping and distinct features de-
pending on the affected step in GPI-anchor biosynthesis. In general,
these disorders are inherited in an autosomal recessive fashion, except
for PIGA, which is X-linked recessive. A recent review of 202 patients
with inherited GPI deficiencies defines many commonalities including
developmental delay, intellectual disability, seizures, and dysmorphic
features (Bellai-Dussault et al., 2018). These defects range from mild to
severe and may depend on the level of residual enzyme activity (Bellai-
Dussault et al., 2018; Tanigawa et al., 2017). A wide variety of con-
genital malformations are also associated with distinct inherited GPI
disorders, including craniofacial, ocular, otologic, gastrointestinal,
cardiac, renal, and skeletal anomalies. Hyperphosphatasia caused by
aberrant secretion of GPI-anchored alkaline phosphatase is a variable
finding in these disorders and a normal level should not exclude this
diagnosis.
Seizures in inherited GPI deficiencies tend to be intractable to
standard therapies and are a major cause of morbidity and mortality.
One proposed mechanism of epileptogenesis in these disorders involves
3
European Journal of Medical Genetics xxx (xxxx) xxxx
defective activity of tissue-nonspecific alkaline phosphatase (TNAP,
encoded by ALPL gene), a GPI-anchored protein that dephosphorylates
pyridoxal phosphate to pyridoxine to cross the neuronal plasma mem-
brane. Pyridoxine is then converted back to pyridoxal phosphate in-
tracellularly, which is an essential cofactor for glutamate decarboxylase
in the synthesis of the inhibitory neurotransmitter, GABA. Mice lacking
TNAP develop seizures due to GABA depletion that are responsive to
vitamin B6 administration (Waymire et al., 1995). Based on this, pyr-
idoxine treatment was attempted and lead to complete seizure resolu-
tion in one patient with bi-allelic PIGO mutations (Kuki et al., 2013).
Unfortunately, there was no clinical or electroencephalographic re-
sponse to an IV pyridoxine bolus in our patient and only transient re-
sponses were observed in other patients described in the literature
(Tanigawa et al., 2017; Xue et al., 2016). This highlights the importance
of defining the mechanism of dysfunctional GPI-anchoring in epi-
leptogenesis to develop more effective therapies.
The PIGO gene encodes one of the ethanolamine phosphate trans-
ferase enzymes that catalyzes the addition of ethanolamine phosphate
to the third mannose residue, which is the site of attachment for pro-
teins on the GPI anchor. The young girl described in this case report
represents the 18th case of bi-allelic PIGO mutations described in the
literature to date and she presents with both overlapping and distinct
features. Table 1 provides a summary of the clinical characteristics of
our patient in addition to these previously reported cases (Krawitz
et al., 2012; Kuki et al., 2013; Morren et al., 2017; Nakamura et al.,
2014; Pagnamenta et al., 2017; Tanigawa et al., 2017; Xue et al., 2016;
Zehavi et al., 2017). Universal features include global developmental
delay and hyperphosphatasia, although mild alkaline phosphatase ele-
vations were observed in some patients with only 10/18 showing le-
vels > 1000 U/L. Seizures were present in 12/18 patients with a typical
onset of < 2 years of age, although 3 of these patients were either de-
ceased or hadn't been assessed beyond 2 years of age. Gastrointestinal
anomalies (10/18) were another common feature, including anal
atresia (6/18; two additional patients with anal stenosis), Hirschsprung
disease (6/18), and esophageal atresia (2/18). Distal digit abnormal-
ities including distal digit hypoplasia (14/18) and nail abnormalities
(10/18) were the most common reported dysmorphisms. Hearing loss
was described in 9/18 patients. Facial dysmorphisms were varied, al-
though it is notable that 6/18 patients were described to have a tented
upper lip and 8/18 children had ear abnormalities.
The most unique characteristic of this case is the complex urogenital
malformations. Our patient had several abnormalities including per-
ipheral renal cysts, dilated tortuous ureters, and significant hydrone-
phrosis that ultimately led to urosepsis and the need for a percutaneous
nephrostomy tube. No other morphologic renal abnormalities have
been reported in patients with bi-allelic PIGO mutations. Interestingly,
congenital hydronephrosis and other renal defects have been observed
in patients with PIGV and PIGN mutations, which also encode enzymes
involved in the processing of sugar moieties on the GPI anchor (Fleming
et al., 2015; Horn et al., 2013). The complete duplication of the vagina
and uterus described above represents a novel feature of inherited GPI
deficiencies.
In fact, the spectrum of congenital anomalies in our patient led to an
initial description of VACTERL association, meeting three criteria in-
cluding anal atresia, TEF/EA, and renal abnormalities. However,
VACTERL association is a diagnosis of exclusion when a formal genetic
diagnosis cannot be reached. Based on the above case, we suggest that
the onset of seizures in the setting of VACTERL features should prompt
a workup for an inherited GPI anchor deficiency with targeted genetic
sequencing panels or via whole exome sequencing. Flow cytometric
analysis of GPI-anchored proteins such as CD16 can also support this
diagnosis. This should be considered even in the absence of hyper-
phosphatasia.
Our patient was found to possess two novel PIGO variants with a
missense mutation (NM_032634.4:c.1352T > G; p(Met451Arg);
Fig. 2A). and one pathogenic frameshift mutation
 Table 1
Clinical features of 18 patients with PIGO deficiency.
Source Current Report Krawitz et al., 2012 Kuki et al., 2013 Nakamura et al., 2014 Xue et al., 2016
A.M. Holtz, et al.

Patient# 1 2 3 4 5 6 7 8
Gender F F F F M M F M
Age 9moa 22moa 12yo 15yo 9yo 19yo 1yoa 21mo
Genotype p.M451R/ p.I464Mfs p.L957F/ c.3069+5G > A p.L957F/ p.L957F/ p.R119W/ p.A834Cfs p.T130N/ p.G430a p.T130N/ p.153S/ p.A452Gfs
p.T788Hfs p.T788Hfs p.G430a
Seizures (onset) Yes (4mo) Yes (1yo) – – Yes (1yo) Yes (7mo) Yes (1yo) Yes (6mo)
Brain MRI Thin corpus callosum, hypoplastic N/A N/A N/A Hypomyelination, abnormal Progressive, diffuse N/A High DWI signal in
cerebellar vermi, optic nerve and signals in basal ganglia to cerebral and globus pallidus and
chiasm, T2 prolongation in basal brainstem cerebellar atrophy dorsal brainstem
ganglia,
thalami, brain stem
Development GDD GDD GDD GDD GDD GDD GDD GDD
Hypotonia + + + + + + + +
Gastrointestinal Anal atresia, recto- vestibular fistula, Anal atresia with fistula, Anal stenosis Anal stenosis Hirschsprung's disease – – Anal atresia
TEF/EA Hirschsprung's disease
Gento-urinary Duplicated vagina anduterus – – – – – – –
Renal Dilated tortuous ureters, Vesico-ureteral reflux – – – – – –
hydronephrosis, peripheral renal cysts
Cardiovascular – ASD, PA stenosis – – Tetrology of Fallot – – –
Hearing loss + + – – + + + –
Ear anomalies Large dysmorphic ear – – – Low-set – – –
Craniofacial anomalies – Left coronal synostosis – – Cleft lip and palate – – Submucosal cleft
Distal digit hypoplasia + + + + + – – +
Nail hypoplasia + + + + + – – –
Facial dysmorphisms Upslanting palpebral fissures, Hypertelorism, long palpebral – – Hypertelorism, High-arched palate, – –

4
epicanthal folds, downturned corners of fissures, tented upper lip, broad blepharophimosis, tented upper lip
mouth, tented upper lip, nasal bridge
microretrognathia
Hyperphosphatasia (U/ Yes (> 1500) Yes (1872) Yes (1381) Yes (1436) Yes (1201–5959) Yes (436–900) Mild/normal Yes (739–943)
L)

Source Tanigawa et al., 2017 Morren et al., 2017 Zehavi et al., 2017 Pagnamenta
et al., 2017

Patient# 9 10 11 12 13 14 15 16 17 18
Gender F M F F F M M F F M
Age 17moa 20moa 9mo 5yo 2yo 13yo 22yo 2.7yoa 5yo 2yo
Genotype p.N370S/ p.A834Cfs p.N370S/ p.A834Cfs p.N370S/ p.G883fs p.M344K/ p.M344K/ p.K1047E/ p.Q430a p.H871P/ p.R604P p.M255I/ p.M255I/ p.M255I p.G238D/
p.G883fs p.G883fs p.M255I p.R436W
Seizures (onset) – – Yes (neonatal) Yes (2yo) Yes (2yo) – Yes (17mo) Yes (10mo) Yes (6mo) –
Brain MRI Normal Hypoplasia of Cerebellar vermis Normal Normal High-intensity Thin corpus callosum, Hypoplastic Hypoplastic corpus N/A, reported
cerebellar vermis and atrophy, white signals in cavum septum corpus callosum, callosum, cortical microcephaly
brain stem matter volume periventricular pellucidum, white mild cortical atrophy, delayed
reduction white matter matter lesions atrophy myelination
Development GDD GDD GDD GDD GDD Language delay, Severe intellectual GDD GDD GDD
mild learning disability
difficulties
Hypotonia – + + + + + + + + +
Gastrointestinal Anal atresia (partial), Anal atresia, recto- EA, Hirschsprung's – – Anal atresia Mild anal prolapse – – Hirschsprung's
Hirschsprung's urethral fistula, disease with pressure disease
disease Hischsprung's disease
Gento-urinary – Cryptorchidism – – – Cryptorchidism Hypogonadism – – –
Renal – – – – – – – – – –
Cardiovascular – – – – – – – – – –
European Journal of Medical Genetics xxx (xxxx) xxxx

(continued on next page)

A.M. Holtz, et al. European Journal of Medical Genetics xxx (xxxx) xxxx

(NM_032634.4:c.1392delinsGA; p(Ile464Mfs*42); Fig. 2B). inherited in

trans. Neither variant is present in the genome Aggregation Database

Yes (418–624)
(gnomAD; Karczewski et al., 2019). SIFT, PROVEAN, PolyPhen-2, and
Pagnamenta
et al., 2017

MutationTaster all predict a deleterious effect of the p.(Met451Arg)

variant. This mutation is found downstream of the catalytic GPI etha-

N/A
+

+
+
nolamine phosphatase transferase domain at the N-terminal portion of
–

–
the 2nd transmembrane domain and affects a highly conserved me-
thionine residue (Fig. 2A–C). Missense mutations both within and

upslanting palpebral
fissures, broad nasal
bridge, blue sclera,
outside of the GPI ethanolamine phosphatase transferase domain can

elongated lashes
Mild (260–490)
Hypertelorism,
cause reduced enzyme activity and compromise protein stability
(Tanigawa et al., 2017). Thus, the p.(M451R) variant likely impairs
Low-set

enzyme activity, especially considering the high degree of phenotypic

overlap between the patient described above and other children with

denotes the patient is deceased. GDD: global developmental delay, TEF/EA: trachea-esophageal fistula/esophageal atresia, ASD: atrial septal defect, PA: pulmonary artery.
–

–
–
Zehavi et al., 2017

bi-allelic PIGO variants. Interestingly, the severity of the phenotypic

Mild (217–241)

presentation correlates with the residual PIGO enzyme activity as de-

fined in functional assays; however, this activity does not correlate with
serum alkaline phosphatase levels or the levels of GPI-anchored pro-
teins measured by flow cytometry (Tanigawa et al., 2017). The ma-
–
–

–
–
–

ternally inherited KRAS variant and paternally inherited MFN2 variant

are unlikely to be contributing to the patient's presentation given the
Morren et al., 2017

lack of features typical of Noonan syndrome and no parental history

related to RASopathies or Charcot-Marie-Tooth Neuropathy type 2A.
Yes (5131)

Patients typically present with one frameshift or nonsense variant,

likely acting as a null allele, and one missense variant with variable
residual enzyme function (Tanigawa et al., 2017). The lack of two null
+
+
–
–

alleles in a patient suggests that residual enzyme activity is required for

high-arched palate

viability. Our patient certainly fits this trend; however, it is important

Yes (2816–5229)
Thick eye brows,
Submucosal cleft

epicanthal folds,

to note that four recently described patients were found to possess ei-
ther homozygous or compound heterozygous missense variants with
relatively severe presentations (Morren et al., 2017; Pagnamenta et al.,
2017; Zehavi et al., 2017). All four patients had severe developmental
+
–
–

delay and 3/4 had seizure disorders (Morren et al., 2017; Zehavi et al.,
2017). The patient in Pagnamenta et al. (p.Gly23Asp/p.Arg436Trp) did
Malformed

upper lip

not have epilepsy as of their last evaluation at 2-years of age

Tented

Mild

(Pagnamenta et al., 2017). Enzyme activity assays demonstrated that

+
–

the PIGO p.Gly238Asp variant had no appreciable enzyme activity

while the p.Arg436Trp had some residual function (Pagnamenta et al.,
Malformed

upper lip

2017). Further functional characterization of PIGO missense variants

Tented

will help to define this genotype-to-phenotype correlation.

Mild
+
–

In conclusion, we describe a novel bi-allelic PIGO mutations pre-

senting with overlapping and distinct features compared to other pa-
Cleft lip and palate

tients described with Mabry syndrome. The severity of the patient's

Tented upper lip

genital and urinary tract malformations extends the phenotypic spec-

Yes (3079)
Malformed

trum of inherited GPI deficiencies. The mechanisms by which mutations

in GPI anchor biosynthesis affect tissue development and promote sei-
zure activity remains largely unknown. Further animal models will be
+

+
+

critical to better define the consequences of aberrant GPI-anchoring in

Tanigawa et al., 2017

Large dysmorphic ear

Upslanting palpebral

nares, micrognathia
fissures, anteverted

disease pathogenesis and provide preclinical models to explore novel

therapeutic approaches.
Cleft palate

Yes (2594)

Financial disclosure
+

+
+

None of authors have financial relationships relevant to this article

Upslanting palpebral

to disclose.
nares, micrognathia
fissures, anteverted
Large dysmorphic

Yes (2816–5229)

Declaration of competing interest

Cleft palate

The authors declare no conflicts of interest.

ear
+

+
+

Acknowledgements
Distal digit hypoplasia

Facial dysmorphisms
Table 1 (continued)

Hyperphosphatasia

We would like to acknowledge the family of the young girl de-

Nail hypoplasia
anomalies
Ear anomalies
Hearing loss

scribed for their loving and compassionate advocacy for their child. We
Craniofacial

(U/L)

also thank them for asking us to write this manuscript to share her story
Source

and to help other children. We also acknowledge all of the physicians,

a

nurses, and other staff at Boston Children's Hospital for their dedication

5
A.M. Holtz, et al.
Fig. 2. Mapping of known PIGO variants. Diagram of PIGO protein showing all known missense (A) and nonsense/frameshift (B) variants described in the literature.
Orange denotes transmembrane domains and blue represents the GPI ethanolamine phosphatase transferase 3 domain. The variants described in this report are
denoted in red. (C) Multi-species alignment of M451 showing conservation of this methionine residue. (For interpretation of the references to colour in this figure
legend, the reader is referred to the Web version of this article.)
and exceptional care. The variants described in this report were iden-
tified as part of the SouthSeq project (U01HG007301) and sequencing
was performed at the HudsonAlpha Institute for Biotechnology in
Huntsville, AL.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.ejmg.2019.103802.
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