Supplemental Text:
A Genome Sequencing Program for Novel Undiagnosed Diseases
Running Title: Genome Sequencing for Unknown Disease Diagnosis
Cinnamon S. Bloss,1 Ashley A. Scott-Van Zeeland,2 Sarah E. Topol,1 Burcu F. Darst,1 Debra L.
Boeldt,1 Galina A. Erikson,1 Kelly J. Bethel,3 Robert L. Bjork,4 Jennifer R. Friedman,5 Nelson
Hwynn,6 Bradley A. Patay,7 Paul J. Pockros,8 Erick R. Scott,1 Ronald A. Simon,9 Gary W.
Williams,10 Nicholas J. Schork,1,11 Eric J. Topol,1,11,12 Ali Torkamani 1, 2,11,13*
1
Scripps Genomic Medicine, Scripps Health, San Diego CA 92037
Cypher Genomics Inc., San Diego CA 92121
3
Division of Pathology, Scripps Clinic, San Diego CA 92037
4
Pediatrics, Scripps Health, San Diego, CA 92037
5
Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego,
CA 92093
6
Division of Neurology, Scripps Clinic, San Diego CA 92037
7
Division of Internal Medicine, Scripps Clinic, San Diego CA 92037
8
Division of Gastroeneterology/Hepatology, Scripps Clinic, San Diego CA 92037
9
Division of Allergy and Immunology, Scripps Clinic, San Diego CA 92037
10
Division of Rheumatology, Scripps Clinic, San Diego CA 92037
11
Department of Molecular and Experimental Medicine, The Scripps Research Institute
12
Division of Cardiology, Scripps Clinic, San Diego CA 92037
13
Department of Integrative Structural and Computational Biology, The Scripps Research
Institute
2
*Correspondence:
Ali Torkamani, Ph.D.
3344 North Torrey Pines Ct.
La Jolla, CA 92037
atorkama@scripps.edu
Detailed Case Descriptions
Reported allele frequency derived from the Exome Aggregation Consortium
(exac.broadinstitute.org/). All coordinates reported are hg19.
In Silico Predictions (codes presented in the following order):
Polyphen2 – Probably Damaging (P), Possibly Damaging (S), Benign (B)
SIFT – INTOLERANT (I), TOLERANT (T)
Condel – Deleterious (D), Neutral (N)
Case descriptions provided on the following pages.
IDIOM1
Description: 15-year-old female of self-reported European ancestry with a lifelong history of
hypotonia, motor delays, abnormal involuntary movements, and sleep disturbance. Gross motor
delays were perceived during her first year of life with sitting at 15 months. At that time, brain
MRI was unremarkable and a diagnosis of cerebral palsy was made. Intermittent choreic
movements of the limbs were noted at 19 months. These movements occurred intermittently
throughout the day at which time they had onset most often with change of posture (e.g., sitting
to standing). They also occurred frequently throughout the night causing significant sleep
disruption for both the participant and her parents. Over the years there has been very slow
mild deterioration in the participant’s ability to ambulate independently. It is unclear whether this
is related to loss of skills versus increased difficulty due to larger body size. Her paroxysmal
movements are more mild during the day than in the past but remain a significant source of
disability during the night time.
Family History: No family history relevant to the presenting condition was noted.
Sequencing: Family-based study (mother, father, and proband)
Confirmed Causal Variant(s):
Gene
Variant
Inheritance
Pattern
Population
Frequency
In Silico
Prediction
Evidence
ADCY5
chr3:123071311 snp G>A
p.R418W
De-Novo
Novel
P,T,D
Confirmed.
PMID: 24700542
Chen YZ, et al. Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia.
Ann Neurol. 2014 Apr;75(4):542-9.
IDIOM2
Description: 33-year-old female of self-reported European ancestry with a two-year history of
atypical lymphoproliferative disease, pancytopenia with autoimmune hemolytic anemia, positive
ANA, splenomegaly with multiple nodules, hepatomegaly, demyelinating brain lesions with facial
paresthesias and visual changes, and pulmonary nodule infiltrates consistent with multi-system
illness and a possible undiagnosed autoimmune disorder. A bone marrow biopsy showed
changes consistent with reactive changes only, and extensive workup is negative except for
Coombs negative hemolytic anemia with high reticulocyte counts and low HPT. ESR, ANA,
PNH were all negative. Infectious disease workups consistently negative. Tissue from an open
lung biopsy initially thought to be consistent with lymphomatous granulomatosis, results were
ultimately read as Bronchiolitis Obliterans Organizing Pneumonia (BOOP). A splenic biopsy
was read as atypical hemophagocytosis, likely reactive to infection or consistent with
autoimmune deficiencies. T and B cell gene rearrangements in spleen tissue and blood were
negative. Ultimately no consensus on diagnosis and no evidence malignancy. 1 year after
enrollment – subject developed lymphoproliferative malignancy.
Family History: Family history potentially significant for cancer (non-hematological).
Sequencing: Family-based study (mother, father, and proband)
Candidate Causal Variant(s):
Gene
GIMPA8
GIMAP8
Variant
chr7:150164006 snp G>T
p.A74S
chr7: 150171600150171634 del
p.N395fs
Inheritance
Pattern
Compound
Heterozygous
Compound
Heterozygous
Population
Frequency
In Silico
Prediction
Novel
B,T,N
0.1%
frameshift
Evidence
GIMAP gene family
influence on lymphocyte
proliferation and survival:
PMID: 17196432
IDIOM3
Description: 19-year-old male with an approximately 15-year history of idiopathic inflammatory
bowel disease. Originally diagnosed with Crohn’s disease at the age of 3 years. Disease has
components of both Crohn’s disease and Ulceritive Colitis. The disease has primarily
manifested itself as diarrhea with an active chronic colitis. Treated without success with
methotrexate, infliximab, adalimumab, and certolizumab. Adverse reactions to 6mercaptopurine. Additional, history of partial complex seizures likely secondary to treatment
with Cimzia. Additional medical history is significant for hepatitis at age 4 years, joint stiffness,
and skin warts.
Family History: No family history relevant to the presenting condition was noted.
Sequencing: Family-based study (mother, father, and proband)
Candidate Causal Variant:
Gene
MST1R
MST1R
Variant
chr3:49940112 snp C>T
p.A311T
chr3:49940517 snp C>T
p.D176N
Inheritance
Pattern
Compound
Heterozygous
Compound
Heterozygous
Population
Frequency
In Silico
Prediction
0.002%
P,T,N/A
0.05%
P,I,N/A
Evidence
See below.
MST1R, otherwise known as RON kinase, inhibits macrophage response to endotoxins and
LPS. Mouse Mice deficient for RON kinase have hyper reactivity to these agents and increased
tissue damage from inflammation (Wilson et al. 2008). The 3p21 locus that contains MST1R
and its ligand MST1 has been associated with IBD (Márquez et al. 2009, Beckly et al. 2008,
Fisher et al. 2008, Latiano et al. 2010).
Wilson CB, Ray M, Lutz M, Sharda D, Xu J, Hankey PA. The RON receptor tyrosine kinase
regulates IFN-gamma production and responses in innate immunity. J Immunol. 2008 Aug
15;181(4):2303-10.
Márquez A, Cénit MC, Núñez C, Mendoza JL, Taxonera C, Díaz-Rubio M, Bartolomé M, Arroyo
R, Fernández-Arquero M, de la Concha EG, Urcelay E. Effect of BSN-MST1 locus on
inflammatory bowel disease and multiple sclerosis susceptibility. Genes Immun. 2009
Oct;10(7):631-5.
Beckly JB, Hancock L, Geremia A, Cummings JR, Morris A, Cooney R, Pathan S, Guo C,
Jewell DP. Two-stage candidate gene study of chromosome 3p demonstrates an association
between nonsynonymous variants in the MST1R gene and Crohn's disease. Inflamm Bowel Dis.
2008 Apr;14(4):500-7.
Fisher SA, et al. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci
implicated in Crohn's disease. Nat Genet. 2008 Jun;40(6):710-2.
Latiano A, Palmieri O, Corritore G, Valvano MR, Bossa F, Cucchiara S, Castro M, Riegler G, De
Venuto D, D'Incà R, Andriulli A, Annese V. Variants at the 3p21 locus influence susceptibility
and phenotype both in adults and early-onset patients with inflammatory bowel disease.
Inflamm Bowel Dis. 2010 Jul;16(7):1108-17.
IDIOM4
Description: 35-year-old female with low-grade fibromyxoid sarcoma.
Family History: No family history relevant to the presenting condition was noted.
Sequencing: Singelton study (proband only)
Candidate Causal Variant(s): No germline variant explaining cancer onset was identified.
IDIOM5
Description: 22-year-old female previously diagnosed with common variable
immunodeficiency, but who lacks a definitive diagnosis. History of Serratia marcescens
infection in infancy, allergic rhinitis, recurrent salivary gland stones, eosinophilic
fasciitis/folliculitis, eosinophilic colitis, and persistent neutropenia. Diagnosed in the first few
months of life with a Serratia marcescens infection affecting the skin and lymph nodes. A
workup for immunodeficiency resulted in an initial diagnosis of common variable
immunodeficiency and started on intravenous gammaglobulin (IVIG). Requires antibiotic therapy
2-3 times per year for clinical acute sinusitis. No instances of pneumonia, meningitis, or
gastrointestinal infections. Evidence of mild bronchiectasis on CT of the chest. History is
remarkable for an episode of eosinophilic fasciitis or folliculitis involving the lower legs, and
lower gastrointestinal bleeding and diagnosis of eosinophilic colitis. Both of these conditions
spontaneously resolved.
Family History: Paternal Uncle with pure red cell aplasia. Low immunoglobulins noted in
mother and sister.
Sequencing: Family-based study (mother, father, proband, and unaffected sibling)
Candidate Causal Variant: No variant plausibly explaining the disorder was identified.
IDIOM6
Description: 44-year-old male with a twelve-year history of extensive painful lipomas, vasculitis
diagnosed with ANCA positive vasculitis Wegener’s granulomatosis.
Family History: No family history relevant to the presenting condition was noted.
Sequencing: Family-based study (mother, father, and proband)
Candidate Causal Variant(s):
Gene
NRIP1
NRIP1
Variant
chr21:16337111 snp G>A
p.R1135C
chr21:16338106 snp G>A
p.S803L
Inheritance
Pattern
Compound
Heterozygous
Compound
Heterozygous
Population
Frequency
In Silico
Prediction
1%
P,I,D
1.5%
B,I,D
Evidence
Gain of function
mechanism implicated.
See below.
One gene, HMGIC, has been described in the genetic etiology of multiple lipomatosis. Gain of
function translocations result in multiple lipomatosis, whereas HMGIC-null mice have a
deficiency in fat tissue and resist diet induced obesity (Anand and Chada, 2000). Similarly,
NRIP1-null mice are lean and resist diet induced obesity (Leonardsson et al. 2004). NRIP1 is a
nuclear protein that interacts with hormone responsive nuclear receptors and is a key regulator
of glucose and lipid metabolism (Rosell et al. 2011) – especially in adipocytes (Debevec et al.
2007). Moreover, lack of NRIP1 in mouse macrophages leads to an inhibition of
proinflammatory pathways (Zschiedrich et al. 2008). These observations are strongly consistent
with a gain-of-function in NRIP1 leading to proliferation of adipocytes and promotion of
proinflammatory pathways – explaining the co-occurance of lipomatosis and Wegener’s
granulomatosis in the subject.
Anand A, Chada K. In vivo modulation of Hmgic reduces obesity. Nat Genet. 2000
Apr;24(4):377-80.
Zschiedrich I, et al. Coactivator function of RIP140 for NFkappaB/RelA-dependent cytokine
gene expression. Blood. 2008 Jul 15;112(2):264-76.
Leonardsson G, et al. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc
Natl Acad Sci U S A. 2004 Jun 1;101(22):8437-42.
Debevec D, et al. Receptor interacting protein 140 regulates expression of uncoupling protein 1
in adipocytes through specific peroxisome proliferator activated receptor isoforms and estrogenrelated receptor alpha. Mol Endocrinol. 2007 Jul;21(7):1581-92.
Rosell M, et al. Role of nuclear receptor corepressor RIP140 in metabolic syndrome. Biochim
Biophys Acta. 2011 Aug;1812(8):919-28.
IDIOM7
Description: 39-year-old female with a complex history of progressive neuropathies, muscle
weakness, Raynaud’s phenomenon, scleroderma syncope and hypermobility. Long-standing
history of bilateral upper extremity numbness and tingling, mainly in the fingers, also spreading
to the axilla area. Vascular specialist excluded the possibility of thoracic outlet syndrome. Over
the years she continued to experience focal weakness of one or another extremity, deep pain,
syncopal episodes and was evaluated for the possibilities of autoimmune disorders, vasculitis,
multiple sclerosis, amyloid, and lymphoma, and POEMS Syndrome with inconclusive results.
She has also suffered multiple allergic reactions with skin eruptions which required steroid
treatment for resolution. She was discovered to have a monoclonal gammopathy which has not
changed over several years. Evaluation for thickened gastric folds led to diagnosis of abnormal
collagen fibers in the GI tract. A unifying diagnosis of scleroderma has been established based
on her history, Raynaud’s, mild sclerodactyly and GI symptomatology. She reports shortness of
breath, atypical chest pains, dizziness while sitting, fatigue, swelling and speeding heart. A
nerve biopsy showed sprouting of nerve fibers and axonal thinning. Serologies have been
negative. Via imaging, a number of incidental anatomical variants have also been discovered in
the abdominal area, including circumaortic left renal vein, different location of the cecum and
right colon, and a non-fully formed appendix.
Family History: Maternal history of Raynaud’s syndrome, neuropathy, thoracic outlet
syndrome, Sjogren’s syndrome, anti-phospholipid syndrome with severe ulcerative wounds, and
chronic diarrhea.
Sequencing: Family-based study (mother, father, and proband)
Candidate Causal Variant(s):
Gene
DST
DST
Variant
chr6:56483052 snp T>C
p.H1927R
(maternally inherited)
chr6:56485496 snp C>G
p.D1112E
Inheritance
Pattern
Population
Frequency
In Silico
Prediction
Compound
Heterozygous
0.4%
N/A,I,N/A
Compound
Heterozygous
0.3%
Evidence
See below.
N/A,T,N/A
DST, otherwise known as dystonin or bullous pemphigoid antigen (BPAG) is an adhesion
junction plaque protein with multiple distinct isoforms. The variants identified in this subject
impact the coiled-coil domain specifically expressed in isoforms BPAG1e (epithelial) and
BPAG1n (neuronal). Mutations in the mouse Dst gene have been previously shown to cause
sensory neuron degeneration and skin fragility (Brown et al. 1995, Guo et al. 1995, Pool et al.
2005, Goryunov et al. 2007). Moreover, a homozygous nonsense mutations in DST have been
implicated in autosomal recessive epidermolysis bullosa simplex in a single individual (Groves
et al. 2010). This individual also displayed neurological abnormalities including headaches and
parasthesiae. Finally, DST mutation has been implicated in hereditary sensory autonomic
neuropathy in a second family (Edvardson et al. 2012).
Brown A, et al. The mouse dystonia musculorum gene is a neural isoform of bullous pemphigoid
antigen 1. Nat Genet. 1995 Jul;10(3):301-6.
Edvardson S, et al. Hereditary sensory autonomic neuropathy caused by a mutation in dystonin.
Ann Neurol. 2012 Apr;71(4):569-72.
Goryunov D, et al. Molecular characterization of the genetic lesion in Dystonia musculorum (dtAlb) mice. Brain Res. 2007 Apr 6;1140:179-87.
Groves RW, et al. A homozygous nonsense mutation within the dystonin gene coding for the
coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal
recessive epidermolysis bullosa simplex. J Invest Dermatol. 2010 Jun;130(6):1551-7.
Guo L, et al. Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration
in stratified epithelia and neurologic degeneration. Cell. 1995 Apr 21;81 (2):233-43.
Pool M, et al. Genetic alterations at the Bpag1 locus in dt mice and their impact on transcript
expression. Mamm Genome. 2005 Dec;16(12):909-17.
IDIOM8
Description: 14-month-old female with unknown gastrointestinal and metabolic disease
coupled with neurological symptoms. Specific symptoms include hypotonia, global
developmental delay, torticollis, mild plagiocephaly, recurring urinary tract infections, recurrent
respiratory infections, multiple ear infections, and suspected seizure activity. Pre-mature birth.
Family History: No family history relevant to the presenting condition was noted.
Sequencing: Family-based study (mother, father, and proband)
Candidate Causal Variant(s): No variant plausibly explaining the disorder was identified.
IDIOM9
Description: 8-year-old female with a complex neurological history global delay, hypotonia,
epileptic encephalopathy, vision impairment, poor modulation of motor movement, blood
pressure and pulse lability, long QT, and potential cerebral folate deficiency. See primary
publication (below) for complete description.
Family History: Maternal history of premature delivery of two children who have global
developmental delays attributed to their prematurity.
Sequencing: Family-based study (mother, father, proband, and unaffected sibling)
Confirmed Causal Variant(s):
Gene
Variant
Inheritance
Pattern
Population
Frequency
In Silico
Prediction
Evidence
KCNB1
chr20:47991056 snp G>T
p.S347R
De-Novo
Novel
P,I,D
Confirmed.
PMID: 25164438
Torkamani A et al. De novo KCNB1 mutations in epileptic encephalopathy. Ann Neurol. 2014
Oct;76(4):529-40.
IDIOM10
Description: 4-year-old female with a complex history of infantile spasms, developmental
delay, gastroesophageal reflux disease, heart defect, short-chain-acyl-CoA dehydrogenase
deficiency, and sensorineural hearing loss. She presented with single transverse palmar
creases bilaterally, posteriorly rotated crimped ears, mild down-slanting palpebral fissures,
possible ptosis, and a prominent forehead. She had a 1/6 systolic murmur, which was later
found by cardiology to be secondary to a patent foramen ovale (PFO) or a secundum atrial
septal defect. At 4 months of age, she was found to be developmentally at risk for poor
receptive communication, expressive communication, fine motor skills, and gross motor skills.
She was found to have very poor total language ability and her development was about a month
behind. A brain MRI was performed that revealed that her ventricles were at the upper limits of
normal, but otherwise was normal. Hearing evaluations revealed Oto Acoustic Emissions test
(OAE) but an abnormal Brainstem Evoked Response (BAER) test, suggesting mild
sensorineural hearing loss in her right ear. At seven months she was observed to have grade IV
vesicoureteral reflux, which has been surgically repaired. She also had abnormal visual
behavior and Gastroesophageal Reflux Disease (GERD). Metabolic tests are consistent with
what is seen in SCAD, but overall symptoms do not fit that diagnosis.
Family History: No family history relevant to the presenting condition was noted.
Sequencing: Family-based study (mother, father, and proband)
Candidate Causal Variant(s):
Gene
Variant
Inheritance
Pattern
Population
Frequency
In Silico
Prediction
SYNPO
chr5:150028651 snp C>T
p.H257N
Compound
Heterozygous
0.5%
S,I,D
SYNPO
chr5:150027874 snp C>A
p.P516S
Compound
Heterozygous
0.3%
P,I,D
chr2:111551725 snp G>A
p.E107K
chr2:111562875 snp C>T
p.S219L
Compound
Heterozygous
Compound
Heterozygous
0.0008%
S,I,D
2.1%
P,I,D
ACOXL
ACOXL
Evidence
K/O mice display
abnormalities in
telencephalic neurons,
reduced long term
potentiation, and
behavioral abnormalities
including hypoactivity,
reduced anxiety, and
learning deficiencies.
PMID: 12928494
May explain the observed
metabolic profile.
IDIOM11
Description: 41 y/o male previously diagnosed with premature, idiopathic coronary artery
disease at age 32. At age 32 he experienced severe angina while completing a marathon and
later learned of his CAD, which has continued to progress despite intervention and a healthy
lifestyle and is now advanced. He has had multiple PTCA (stent) procedures. He has had
normal ECGs in sinus rhythm noting only non-specific T wave abnormality. Exercise stress
echo in January showed normal wall thickness and ejection fraction, trivial mitral valve
regurgitation, no aortic valve stenosis or regurgitation. He is a non-smoker, no history of drug
use, years of following low-fat diet, routinely exercises. No family history of Tangier’s disease,
Kawasaki’s disease or mediastinal radiation.
Family History: His father, paternal uncle and paternal grandmother all have a history of
premature coronary artery disease.
Sequencing: Family-based study (mother, father, proband, paternal uncle, paternal
gradmother, unaffected sibling)
Candidate Causal Variant(s):
Gene
Variant
TDG
chr12:104376972 snp C>T
p.R225*
Inheritance
Pattern
Dominant –
shared by all
affected
family
members
Population
Frequency
In Silico
Prediction
Evidence
Novel
Nonsense
See below
TDG is involved in maintaining epigenetic stability in lineage committed cells, especially
vascular endothelial cells (Cortázar D et al. 2011). K/O is lethal due to vascular defects.
Specifically TDG-null embryos exhibit specific patterning defects of the developing heart, with
the most significant abnormalities seen in the outflow tract (OFT), vasculogenesis defects of
dorsal aortae, carotid arteries and branchial arteries and generalized defect of angiogenesis,
particularly evident as altered branching of the internal carotid and the coronaries (Cortellino et
al. 2011).
Cortázar D, et al. Embryonic lethal phenotype reveals a function of TDG in maintaining
epigenetic stability. Nature. 2011 Feb 17;470(7334):419-23.
Cortellino S, et al. Thymine DNA glycosylase is essential for active DNA demethylation by linked
deamination-base excision repair. Cell. 2011 Jul 8;146(1):67-79.
IDIOM12
Description: 20 and 22 year old brothers, both experiencing extreme muscle and general
fatigue, inflammation, pain, and inability to concentrate rendering them unable to continue their
university studies and diminishing their quality of life. Symptoms first presented as a “fatiguetype weakness” and pain in their lower legs at the ages of 14 and 18, respectively. The
symptoms have now progressed to legs, arms, eyes, and throughout their entire bodies.
Abnormal gait patterns with constant activity and continuous firing of various muscles has been
observed. Ambulation is now limited to 100 meteres with a cane and/or ankle braces, due to
immediate fatigue in the legs. Convergence insufficiency has been observed in both eyes and
requires corrective prism lenses for reading. Mild to severe inflammation observed throughout
the body.
Family History: Father with idiopathic angioedema.
Sequencing: Family-based study (mother, father, and affected brothers)
Candidate Causal Variant(s): No variant plausibly explaining the disorder was identified.
IDIOM13
Description: 5 week male with abnormal neurological exam, including nystagmus, excessive
startle and intermittent tremors. Abnormal MRI. Brother presented at approximately 3 months of
age with seizures - deceased at 19 months with unknown neurodegnerative condition.
Deceased brother had severe epileptic encephalopathy, developmental arrest, hearing and
visual impairment, olivodentate dysplasia, possible myopathy/cardiomyopathy.
Family History: Deceased brother with similar phenotype.
Sequencing: Family-based study (mother, father, and proband)
Candidate Causal Variant(s): No variant plausibly explaining the disorder was identified.
IDIOM14
Description: 10 year old female with recurrent fevers of unknown origin. Fevers up to 106.3
Fahrenheit, difficult to control with medication. Urine organic acids not suggestive of mevalonic
kinase deficiency. Muckle-Wells, NOMID, CINCA, Familial Cold Autoinflammatory syndrome,
and Mediterranean Fever, Familial Hibernian Fever all ruled out via targeted sequencing. Fair
skin and easily bruised. Recurrent infections. Sepsis in mother.
Family History: Mother and maternal grandmother with fevers throughout life.
Sequencing: Family-based study (mother, father, proband, and maternal gradmother)
Candidate Causal Variant(s):
Gene
Variant
LYST
chr1:235969465 snp G>T
p.H991N
Inheritance
Pattern
Dominant shared by all
affected
family
members
Population
Frequency
In Silico
Prediction
Evidence
Novel
P,I,D
See below
Mutations in LYST cause Chediak-Higashi syndrome – a disorder that affects the immune
system and predisposes individuals to persistent infections starting early in infancy. ChediakHigashi syndrome is inherited in an autosomal recessive manner, whereas the mutation in the
family is heterozygous in all affected individuals; however Chediak-Higashi syndrome is more
severe than the presenting phenotype in the proband suggesting that the LYST mutation may
cause a mild form of the syndrome (OMIM:606897). Affected individuals typically have fair skin
and light-colored hair, often with a metallic sheen and blood clotting deficiency that leads to
easy bruising and abnormal bleeding. This is consistent with the proband’s described phenotype
and suggests incomplete Chediak-Higashi syndrome via a single missense mutation.
IDIOM15
Description: Hypertrichosism, intellectual disability, and a dilated aorta.
Family History: No family history relevant to the presenting condition was noted.
Sequencing: Family-based study (mother, father, and proband)
Confirmed Causal Variant(s):
Gene
Variant
Inheritance
Pattern
Population
Frequency
In Silico
Prediction
Evidence
ABCC9
chr12:21995261 snp G>A
p.R1154W
De-Novo
Novel
P,I,D
Known Pathogenic.
Clinvar:RCV000024624
N-of-1 Trial Description
Consent: A separate informed consent under the original IRB approved IDIOM trial was attained
from IDIOM1 and parents for the monitoring trial.
Trial Design:
An Actigraph device (wActiSleep-BT Monitor, Actigraph, LLC., Pensacola, FL) was worn on the
right ankle throughout the day to monitor for abnormal movements during sleep. A period of
abnormal movements was defined as a consecutive period of at least 60 second where the
vector magnitude was greater than zero. The parents of the subject were instructed connect the
device weekly to a computer to charge the device and to transfer data to a secure server.
Movement data was extracted with the ActiLife 6 software application (Actigraph, LLC.,
Pensacola, FL).
An N-of-1 style trial to monitor night time abnormal movements was initiated. Trial design
included:
1. A one month run-in period where current treatments were tapered off under the
supervision of the treating physician.
2. A baseline period of two weeks to collect baseline movement data (displayed in Figure 1
of the main manuscript).
3. Treatment periods of 1 month – which included taper on and taper off periods for
introducing new compounds. The desired target was 2 weeks at a stable dosage per
compound. Compounds that should theoretically counteract an ADCY5 gain of function
were selected for the trial (ropinirole, carbamazepine, tetrabenazine, diazepam).
4. Washout periods of at least 2 weeks sufficiently long to ensure that ~97% elimination of
each compound (5 half-lives) was achieved.
The trial was halted, upon request from the participants, after resolution of the abnormal
movements during treatment #1 (diazepam).