A Novel Loss-of-Function Variant in SETBP1 Causing Autosomal Dominant Mental Retardation 29 in an Asian Indian Male Child
Asodu Sandeep Sarma1, Shivangi Wagh1, Ashwin Dalal1, Prajnya Ranganath1,2 1Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India 2Department of Medical Genetics, Nizam’s Institute of Medical Sciences (NIMS), Hyderabad, India Correspondence to: Dr Prajnya RanganathEmail:prajnyaranganath@gmail.com
1 Abstract
Heterozygous gain-of-function variants in the SETBP1 gene are known to cause Schinzel-Giedion syndrome, a multiple
malformation condition with typical facial dysmorphism. Heterozygous, loss-of-function variants in the same gene have
been recently identified to cause a very rare genetic disorder with a less severe phenotype characterized by mild
dysmorphic features, mild to moderate intellectual disability with speech delay and epilepsy, referred to as autosomal
dominant mental retardation 29. Here, we describe a novel loss-of-function variant c.2622del; p.(Asp874GlufsTer87) in the
SETBP1 gene identified through exome sequencing, in an Asian Indian male patient with facial dysmorphism, global
developmental delay, and seizures.
SETBP1 (OMIM * 611060), located on chromosome 18q21.1, encodes an oncogene-binding protein and binds to SET
domains that are involved in methylation of lysine residues on histone tails and ubiquitously expressed in all tissues
(Hoischen et al., 2010). Germline, de novo heterozygous gain-of-function (GoF) variants in SETBP1 cause a rare
neurodevelopmental disorder characterized by typical craniofacial dysmorphism including severe midface retraction,
congenital heart defect, hydronephrosis, clubfeet, hypertrichosis, epilepsy, and profound neurodevelopmental delay, which
is referred to as Schinzel-Giedion midface retraction syndrome (SGS; OMIM #269150) (Hoischen et al., 2010; Schinzel
and Giedion, 1978). Heterozygous loss-of-function (LoF) variants in the same gene, have been recently
identified to cause a phenotype that is distinct from SGS, with milder intellectual disability and expressive
speech impairment, which is referred to as autosomal dominant mental retardation-29 (MRD29; OMIM #
616078), SETBP1 LoF syndrome, or SETBP1 haploinsufficiency disorder (Filges et al., 2011). There are
only few reports on LoF variants in the SETBP1 gene causing MRD29, and none from the Asian Indian
population.
3 Clinical Details
Here, we describe this 2-years-3-months-old male child, the only offspring of normal nonconsanguineous parents, who was
referred for evaluation of global developmental delay and seizures. He was born at term gestation with a
birth-weight of 2.5 kilograms, through an emergency Caesarean section, done for non-progress of labour. There
were no adverse events in the antenatal or neonatal periods. He was noted to have delay in attainment
of milestones from early infancy. Stable head control was attained at 6 months, rolling over from supine
to prone position at 7 months, sitting without support by around 16 months, standing without support
by 20 months, and walking without support by 24 months. At the time of presentation at 27 months of
age, he had not attained the ability to run or climb stairs. He had attained cooing by around 6 months,
monosyllabic speech by around 15 months, and bisyllabic speech by 24 months; meaningful words had not been
attained at the time of evaluation at 27 months. He was able to comprehend simple commands such as when
asked to move his hands, and imitate simple actions such as waving goodbye. Bowel and bladder control
had not been attained. Developmental quotient (DQ) assessment revealed the motor development to be
corresponding to around 12 months, speech & language to around 10 months, and social development to around 18
months.
There was an episode of lower respiratory tract infection requiring hospitalization and administration of
intravenous antibiotics for 1 week, at 6 months of age. Seizures started at the age of 12 months, and he had
recurrent generalized tonic-clonic seizures, which could be controlled only after therapy with two antiepileptic
drugs i.e., levetiracetam and phenytoin, was started. There were no similarly affected individuals in the
family.
On examination, his anthropometric measurements were as follows: length was 86 cm (-1 SD), weight was 11 kgs (-1.6
SD), and head circumference was 48 cm (-1.3 SD) [standard deviations (SDs) mentioned with reference to the mean
anthropometric measurements for age for normal Asian Indian male children]. He was noted to have craniofacial
dysmorphism in the form of mild dolichocephaly, a prominent forehead, frontal bossing, thick arched eyebrows with
medial flare, periorbital fullness, down-slanting palpebral fissures, mild ocular hypertelorism, prominent infraorbital
creases, low-set ears, depressed and wide nasal bridge, wide and bulbous tip of nose, prominent nasolabial
folds, thin upper lip, and a prominent broad chin (Figures 1A & 1B). Neurological examination was
normal except for mild hypotonia of both lower limbs and a developmental quotient (DQ) of around 50%
in all domains. Per abdominal, cardiovascular, respiratory, and musculoskeletal system examination was
normal.
Figure 1: Clinical photographs of the proband (A. frontal view & B. lateral view) showing facial dysmorphic
features in the form of mild dolichocephaly, prominent forehead, frontal bossing, thick arched eyebrows with medial
flare, periorbital fullness, down-slanting palpebral fissures, mild ocular hypertelorism, prominent infraorbital
creases, depressed and wide nasal bridge, wide and bulbous tip of nose, prominent nasolabial folds, low-set ears,
thin upper lip, and prominent chin.
Complete hemogram, liver function tests, serum creatinine, serum electrolytes, serum creatine phosphokinase, and
serum calcium and phosphorus, were normal. Radiographs of the chest and of the left hand and wrist were normal, with
the bone age corresponding to around 2 years. Thyroid function tests which had been done initially at the age of 6
months, at the time of hospitalization for the respiratory infection, had shown a borderline low level of thyroid stimulating
hormone (TSH) of 0.5 mU/L (reference range 0.55 – 5.3 mU/L); however, repeat TSH and free thyroxine (T4) assays
done at 7 months of age, and again at 2 years 3 months, were in the normal range. Magnetic resonance imaging (MRI) of
the brain did not show any specific abnormality.
As no specific etiology could be ascertained clinically, whole-exome sequencing was done for the child. Genomic DNA
was isolated from blood lymphocytes of the proband using the QIAamp DNA Blood Mini kit (Qiagen, Germany) and
exome enrichment was done using the TruSeq exome capture kit (Illumina, USA). The captured library was sequenced to
mean 100X coverage on Illumina HiSeq2000 sequencing platform (Illumina, USA). Exome sequence analysis revealed a
total of 12,0231 variants. After stringent filtering and clinical correlation, a likely pathogenic novel variant was identified
in the SETBP1 gene, NM_015559.2:c.2622del:p.(Asp874GlufsTer87) (Figure 2A). The variant is absent in the
population databases 1000 Genomes and gnomAD, and also in the in-house database of 1400 exomes. This variant is also
not reported in ClinVar, even though a proximal missense variant c.2621A>G; pAsp874Gly, is listed as a pathogenic
variant. It is predicted to be disease-causing by MutationTaster. Sanger sequencing confirmed the heterozygous status
of the variant in the proband (Figure 2B). The variant was confirmed to be absent in both the normal
parents through targeted Sanger sequencing (Figures 2C & 2D), indicating that it is most likely a de novo
variant. The novel SETBP1 variant was interpreted using the American College of Medical Genetics and
Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines (Richards et al., 2015), and was
classified as pathogenic based on the following ACMG-AMP criteria: PM2, PP3, PM5, PM4, PVS1, and
PS2.
AB
CD
Figure 2: A. Integrative Genomics Viewer (IGV) screenshot showing the heterozygous variant c.2622del in
SETBP1 (NM_015559.2) in the proband; B. Sanger sequence chromatogram of the proband showing the
heterozygous variant c.2622del in SETBP1; C. & D. Sanger sequence chromatograms of the parents of the
proband showing absence of the variant c.2622del in SETBP1.
The child was thus diagnosed to have SETBP1-associated autosomal dominant mental retardation 29. The parents
were advised to continue the antiseizure medications, as well as developmental therapy and speech therapy for the child,
on a regular basis, and 3 monthly follow-ups for assessment of growth and development were suggested. Though this
pathogenic variant is most likely of de novo origin in the proband, the likelihood of gonadal mosaicism for this variant in
either parent cannot be ruled out; therefore, there may be an empiric risk of recurrence of around 1% in subsequent
offspring of the parents. This, along with the option of prenatal genetic testing for their future pregnancies, was conveyed
to the parents.
4 Discussion
Schinzel and Giedion first described the phenotype of SGS in 1978 (Schinzel and Giedion, 1978), but the
causative gene mutations were identified much later through exome sequencing of 4 affected individuals by
Hoischen et al. in 2010 (Hoischen et al., 2015). All the SGS-causing variants that have been reported till date
have been found to be missense gain-of-function (GoF) variants and confined to exon 4 of the gene. In
2011, Filges et al. reported a less severe disease phenotype when compared to SGS, caused by heterozygous
loss-of-function (LoF) variants in SETBP1; this condition was designated autosomal dominant mental retardation-29
(MRD29) (Filges et al., 2011). The LoF mutations in SETBP1 that have been reported to cause MRD29
include contiguous gene deletions (Marseglia et al., 2012; Coe et al., 2014), heterozygous deletion including
SETBP1 exclusively (Filges et al., 2011), small indels, and stop-gain variants (Leonardi et al., 2020), which are
distributed throughout the gene, unlike the SGS-causing missense mutations which are localized to the hotspot
region. In addition, while germline GoF and LoF variants in SETBP1 are associated with SGS and MRD29
respectively, somatic mutations in SETBP1 have been implicated in myeloid malignancies (Makishima et al.,
2013).
Patients with SETBP1-associated autosomal dominant mental retardation (MRD29) have been reported to have
delayed motor development, delayed speech, attention deficit hyperactivity disorder (ADHD), and mild to moderate
intellectual disability; severe intellectual disability and seizures have also been reported in a few patients. These patients
also have variable and subtle craniofacial dysmorphism including dolichocephaly, elongated facies, a high forehead, arched
eyebrows, down-slanting palpebral fissures, hypertelorism, periorbital fullness, low-set ears, wide nasal bridge, upturned
nasal tip, smooth philtrum, thin and tented upper lip, and mild micrognathia (Coe et al., 2014; Leonardi et al., 2020).
The phenotype is usually less severe than that of Schinzel-Giedion syndrome, which is caused by GoF variants in
the same SETBP1 gene, and is characterized by severe intellectual disability, coarse facies with severe
midface hypoplasia, multiple congenital malformations including abnormalities of the skull, distal phalangeal
hypoplasia, genitourinary and renal malformations, and congenital cardiac defects, and an increased risk of
neuroepithelial neoplasia. Therefore, unlike for Schinzel-Giedion syndrome, a gestalt diagnosis is usually not possible
for MRD29. However, detailed reverse phenotyping following identification of putative causative variants
through NGS-based testing often helps in corroborating the diagnosis. Our patient, for example, on reverse
phenotyping was found to have most of the dysmorphic features previously reported with SETBP1-associated
MRD29, in addition to motor and speech delay, and seizures requiring two antiepileptic drugs for adequate
control.
Till date, only around 20 patients with MRD29 due to LoF mutation in SETBP1 have been reported
across the world (Filges et al., 2011; Coe et al., 2014; Hamdan et al., 2014; Eising et al., 2019; Leonardi et
al., 2020). To the best of our knowledge, this is the first report of MRD29 in a patient of Asian-Indian
origin.
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