Ciliopathies
Your Clinical Practice
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Use the power of our genetic testing to identify
Ciliopathies and related disorders
ADVANCE YOUR CLINICAL PRACTICE
Ciliopathies – Almost every organ in the body can be affected
1
Ciliopathies are genetic conditions that result in cilia not functioning adequately. Ciliopathies affect multiple
systems causing blindness, deafness, intellectual disabilities, polydactyly, cystic kidney, chronic respiratory
infections, kidney disease, heart disease, infertility, obesity and diabetes.
Retinal Defect/
Degeneration
Hydrocephalus/
Mental
Retardation
Craniofacial
Defect
Ribs/Thoracic
Skeleton
Defect
Cardiac
Defect
Lungs or
Airway
Defect
Liver Cysts
Pancreatic
Cysts
Cystic
Kidneys
Pelvic Bone
Defect
Polydactyly
Sterility or
Genital Defect
Ciliopathies are an emerging class of multisystemic human genetic disorders. Below are the more well
characterized Ciliopathies.1
Ciliopathy
Clinical Features
Inheritance
Primary ciliary dyskinesia (PCD)/ Chronic sinusitis, bronchiectasis and infertility with situs inversus
Autosomal Recessive
Kartagener syndrome (KS)
(KS only) and occasional hydrocephalus (PCD)
Retinal dystrophy, blindness or severe visual impairment
Leber congenital amaurosis (LCA) such as sensory nystagmus, amaurotic pupils and absent
electroretinogram signal
Autosomal Recessive
Bardet-Biedl syndrome
Obesity, diabetes, polydactyly, mental retardation, cystic kidney,
retinitis pigmentosa, hypogenitalism and situs inversus
Autosomal Recessive
Joubert syndrome (JBTS)/JBTSrelated disorder (JSRD)
Hypotonia, ataxia, psychomotor delay, oculomotor apraxia,
retinal degeneration and mental retardation. Occipital
encephalocele, polymicrogyria, cystic kidney, hepatic fibrosis and
polydactyly (JSRD)
Autosomal Recessive
Senior-Loken syndrome
Patients present with retinal involvement (manifesting with either
Leber congenital amaurosis or progressive retinal dystrophy) and Autosomal Recessive
nephronophthisis.
Renal cysts, hepatic fibrosis, central nervous system
Meckel-Gruber syndrome (MKS) malformations, polydactyly, liver malformations, laterality
defects, cardiac
Autosomal Recessive
Oral-facial-digital syndrome
type I (OFD1)
Craniofacial malformations, postaxial polydactyly, central
nervous system defects and cystic kidney (15%)
X-linked Dominant
Nephronophthisis (NPHP)
Triad of tubular basement membrane disruption,
tubulointerstitial nephropathy, corticomedullary cysts.
Pancreatic/hepatic fibrosis, situs inversus, retinitis pigmentosa,
cerebellar vermis hypoplasia, oculomotor apraxia and mental
retardation (~10%)
Autosomal Recessive
ADVANCE YOUR CLINICAL PRACTICE
Benefits of a Ciliopathy Genetic Diagnosis2
• Reduce the burden and disruption of a “diagnostic odyssey” for families
• The identification of a new gene can also reduce misdiagnosis or late diagnosis
• Proper care pathways for ciliopathy patients
• Prioritize those patients that can most benefit from future targeted therapies
Simplifying the Ciliopathy Genetic Diagnosis
Transgenomic offers a Next-Generation Sequencing (NGS) test for 57 reported Ciliopathy disease-causing genes.
This provides the efficiency of a NGS panel that tests many known disease-causing genes with a single test.
Test
Description
Turnaround Time
Ciliopathy NGS Panel
Sequence analysis of 57 reported Ciliopathy disease-causing genes
12 weeks
Whole Exome Sequencing
The patient’s exome will be sequenced to an average depth of 100X
with a minimum depth of coverage of 85X. Over 97% of the exome
will be sequenced to a depth of 10X.
12 weeks
Ciliopathy NGS Panel – Coverage for a Confident Diagnosis
The Ciliopathy NGS Panel covers >99% of the genes at >20X with an average depth of 137X
Genes Analyzed by the Ciliopathy NGS Panel
ACVR2B, B9D1, AHI1, ARL6, ARL13B, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS12, CEP290, C5orf42,
CC2D2A, CCDC39, CCDC40, CEP41, CFTR, DNAAF1, DNAAF2, DNAAF3, DNAH11, DNAH5, DNAI1, DNAI2,
DNAL1, FOXH1, GDF1, GLIS2, INPP5E, INVS, IQCB1, LEFTY2, MKKS, MKS1, NEK8, NKX2-5, NME8, NODAL,
NPHP1, NPHP3, NPHP4, OFD1, RPGR, RPGRIP1L, RSPH4A, RSPH9, SDCCAG8, TCTN2, TIMEM67, TMEM138,
TMEM216, TMEM237, TRIM32, TTC8
Disorders covered3
Joubert syndrome, Nephronophthisis, Bardet-Biedl syndrome, Meckel-Gruber syndrome, Orofaciodigital syndrome,
Leber Congenital Amaurosis, Senior-Loken syndrome, Primary Cilia dyskinesia, Retinitis pigmentosa, COACH
syndrome, Heterotaxy-visceral-4-autosomal, Acvr2b-related visceral heterotaxy, Cystic Fibrosis, Idiopathic
bronchiectasis, FOXH1-related Holoprosencephaly, Septopreoptic holoprosencephaly, Conotruncal heart
malformations, Right atrial isomerism, Acute Megakaryoblastic Leukemia without Down Syndrome, Left-right
axis malformations, Lefty2-related visceral heterotaxy, McKusick-Kaufman syndrome, Renal-hepatic-pancreatic
dysplasia, Ventricular septal defect, Hypoplastic left heart syndrome, Heterotaxy visceral, Situs inversus, SimpsonGolabi-Behmel syndrome-type 2, Sinorespiratory infections with or without deafness, Muscular Dystrophy, LimbGirdle-type 2h
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Result Report:
Simple and Concise
Transgenomic provides reports
that are clear and concise,
including clinical interpretations
and recommendations.
Ciliopathy NGS Panel Test Report
(CONFIDENTIAL)
PHYSICIAN
Physician’s Name:
Hospital/Institution:
Mailing Address:
Specimen Type:
Draw Date:
Receive Date:
Report Date:
SPECIMEN
Patient’s Name:
Date of Birth:
Patient ID:
Gender: Male
Requisition #:
Our reports also discuss our
comprehensive methodology
and any test-related limitations.
PATIENT
TEST RESULT SUMMARY
Report inheritance.
Patient Name:
Patient has a predicted deleterious variant in OFD1, a geneContinuation
with X-linkedofdisease
This genotype could be consistent with Joubert syndrome, Oral-facial-digital syndrome, or
Golabi-Behmel syndrome. Clinical correlation is required.
callosum agenesis, cerebellar agenesis with or without Dandy-Walker malformation), and kidney (polycystic kidney
disease).
As many
as 50% of disease
individuals with
OFD1 have some degree of intellectual disability, which is usually mild.
Patient is a carrier for one variant in CEP290, a gene with
autosomal
recessive
1
Almost
all affectedrecessive
individuals disease
are female. Joubert syndrome 10 is characterized by a distinctive cerebellar and brain
inheritance. Single heterozygous mutations in genes with
autosomal
stem
malformation
called
the
molar
tooth
sign
(MTS), hypotonia, and developmental delays. Carrier females are not
inheritance are not expected to cause
disease.
2
affected. Simpson-Golabi-Behmel syndrome, type 2, is characterized by developmental delays, macrocephaly, and
ciliary dysfunction. Carrier females are not affected.
3
1.
Gene
OFD1
DNA a
Change
c.2398A>T
Protein
Change
p.Arg800*
dbSNP
b
rsID
Associated
Disease
---
Joubert syndrome
10; Oral-facialdigital syndrome 1;
Simpson-GolabiBehmel syndrome,
type 2
OMIM
Toriello and Franco. Revised 2013. Oral-Facial-Digital Syndrome Type I. Gene reviews. http://www.ncbi.nlm.nih.gov/books/NBK1188/.
PubMed 20301367
2. Parisi and Glass. Revised 2013. Joubert Syndrome and Related Disorders. Gene reviews. http://www.ncbi.nlm.nih.gov/books/NBK1325/.
c
d
PubMed
20301500
Inheritance
Zygosity
Classification
3. Budny et al. 2006. A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oralfacial-digital type I syndrome. Hum Genet. 120:171-8. PubMed 16783569
300804;
Predicted
is of unknown
significance, meaning that although it may cause disease when accompanied by a
311200; The variant
XL in CEP290
Heterozygous
Deleterious
300209 deleterious mutation on the other allele, it may instead be a benign, rare variant. This variant have not been reported in
the literature or observed at Transgenomic. In the absence of additional biochemical and functional information, the
clinical significance of this variant remains unknown. The recessive nature of this gene suggests that a patient would
two alleles to develop disease. This variant has not been confirmed by Sanger
sequencing.
require
a mutation
on each
of the
SINGLE VARIANTS IN GENES WITH AUTOSOMAL RECESSIVE INHERITANCE
(not confirmed
by Sanger
Sequencing)
Bardet-Biedl
syndrome 14;
209900;
RECOMMENDATIONS
Joubert syndrome
610188;
5; Leber congenital
611755;
AR
Heterozygous
VUS
CEP290
c.5255G>A
p.Arg1752Gln
116469117
amaurosis 10;
Due
to
the
detection
of
genetic
variation
of
potential
clinical relevance in this patient, the involvement of a geneticist or
611134;
Meckel syndrome
610189 genetic counselor may be helpful for the patient or family members.
4; Senior-Loken
syndrome 6
a
1. The patient has a pathogenic variant of in OFD1, a gene with X-linked disease inheritance. For further evaluation,
The positions listed correspond to the following transcripts: OFD1, NM_003611.2; CEP290, NM_025114.3
b
All variants with dbSNP rsID numbers have minor allele frequencies less than 0.5% unless otherwise stated.
we recommend analysis of parental samples, which may help determine the clinical significance of this alteration.
c
AD=Autosomal Dominant; AR=Autosomal Recessive; XL=X-Linked
d
VUS=Variant of Unknown Significance
INTERPRETATION
If you have any questions about the test result or recommendations, please contact [email protected].
If family testing is ordered, only the OFD1 variant will be included unless otherwise indicated on the requisition. To order
The patient has a predicted deleterious variant in OFD1, a gene with X-linked
disease
The patient
also carries
testing
for inheritance.
family members
of this patient,
use the following code on the test requisition and list the variants to be tested:
one variant in CEP290, a gene with autosomal recessive disease inheritance. Note that large deletions and duplications
cannot be effectively characterized by this method, nor are all genes effectively amplified. Single variants of unknown
significance in genes with autosomal recessive inheritance are not confirmed by Sanger sequencing. If clinical suspicion
for one of these diseases is strong, further studies of these genes may be warranted.
GPI-HT000XXXXX
OFD1 Arg800* – Predicted Deleterious Variant. This variant creates a premature stop codon and is therefore predictedMETHODS AND LIMITATIONS
to disrupt normal protein function. This variant has not been reported in the literature or observed at Transgenomic.
Clinical correlation is required.
The Transgenomic Ciliopathy NGS Panel tests for variants in 57 genes that have been identified as causing Ciliopathies.
This test is performed jointly between Transgenomic, and the Clinical Research Sequencing Platform, BROAD Institute of
Mutations in OFD1 (oral-facial-digital syndrome 1) cause X-linked dominant
Oral-facial-digital
syndrome
X-linked MA, 02141; Telephone: 617-714-7000, CLIA # 22D2055652. Sequencing is
Harvard
and MIT, 320
Charles 1,
St,and
Cambridge,
recessive Joubert syndrome 10, and Simpson-Golabi-Behmel syndrome,performed
type 2. Oral-facial-digital
syndrome
type
I
by the BROAD Institute
using
a solution-based
hybrid capture of the coding exons of the entire exome, and
®
(OFD1) is associated with dysfunction of primary cilia and is characterized by the following abnormalities:
oral (lobed
sequencing
on the Illumina
HiSeq platform.
tongue, hamartomas or lipomas of the tongue, cleft of the hard or soft palate,
accessory gingival
frenulae, hypodontia,
and Data analysis and interpretation is performed by Transgenomic, and all
Deleterious,
Predicted
Deleterious
or
VUS
variants
in
dominant
and X-linked genes are confirmed by Sanger sequencing
other dental abnormalities), facial (widely spaced eyes or telecanthus, hypoplasia of the alae nasi, median cleft or
Transgenomic.
Single
variants of
in genes
pseudocleft upper lip, micrognathia), digital (brachydactyly, syndactyly of by
varying
degrees, and
clinodactyly
the fifthwith AR inheritance are not confirmed by Sanger sequencing. Variants are
classified
by
comparison
with
reference
sequences
and
through
review of published literature, public variant databases,
finger; duplicated hallux [great toe]; preaxial or postaxial polydactyly of the hands), brain (intracerebral cysts, corpus
and Transgenomic’s sequencing results. In general, dominant and X-linked variants with a minor allele frequency (MAF)
0.2% and recessive variants with a MAF 0.5% in ostensibly healthy control populations are considered polymorphisms.
1 of 3PolyPhen-2 (trained with the HumVar dataset) (Nat Methods, 2010, 7:248-9,
Using Alamut (v2.2) Interactive Biosoftware,
2009, 4(7): 1073-81, PMID 19561590), and Mutation Taster (Nat Methods, 2010,
Transgenomic
5 Science Park New Haven, Connecticut PMID
06511 20354512), SIFT (Nat Protoc,
877.274.9432
7(8):575-6, PMID 206760750) in silico analyses and Ensembl orthologue alignments (Hum Mutat, 2008, 29(11): 1327-36,
PMID 18951440) were used to predict the pathogenicity and evolutionary conservation of all nonsynonymous variants of
unknown significance. The accuracy of the predictions made by these programs have not been established in the context
of these specific genes. This test will not detect certain types of sequence variation including large deletions and
duplications, copy number variations, triplet repeat expansions, and intronic variants outside of 10bp from the intron-exon
border. In addition, this technology is limited in its ability to detect small insertions and deletions, and variants occurring in
regions with high sequence identity to other regions of the genome. Some regions of targeted genes cannot be effectively
amplified and sequenced as a result of technical limitations of the assay. Rare sequence variants, regions of GC-rich
structure, or repetitive sequences may interfere with analysis. This report includes any detected variants categorized as
deleterious, predicted deleterious, possibly deleterious, and variants of unknown significance. Variants that have not been
reported in the literature and are predicted to be benign by all four prediction programs described above have been
classified as likely benign and not reported. Please contact the laboratory for information about these excluded variants.
These results should be interpreted in the context of family history, clinical findings, and other laboratory data as
appropriate. Interpretation and classification of variants are subject to change in light of new evidence.
2 of 3
Transgenomic
5 Science Park New Haven, Connecticut 06511
877.274.9432
DISCOVER THE POWER OF OUR GENETIC TESTING
We are committed
to advancing your
clinical practice
Transgenomic offers:
Genetic testing panels
We provide comprehensive genetic testing panels available for
Ciliopathies and associated disorders.
Professional support and resources
Our scientific and genetic counseling team is here to support
you with everything from test selection to outcomes research,
analysis, and interpretation.
Test reports
Clear and comprehensive genetic testing reports assist you in
making effective and timely patient management decisions.
References:
1. Lee, E.J., et al. A systems-biology approach to understanding the ciliopathy disorders. Genome Medicine 2011, 3:59
2. Johnson, C.A., et al. Ciliopathy disease gene identification by whole exome medical resequencing. http://gtr.rcuk.ac.uk/project/6C01E8A5-A5FB-45F68F0A-B9665762F459.
3. Orphanet. http://www.orpha.net/consor/cgi-bin/index.php.
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