Genetics of Inherited Axonopathies
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Stephan Züchner discusses major developments in human genetics including improved genome sequencing capabilities and declining costs. He summarizes research on inherited axonopathies like hereditary spastic paraplegias and Charcot-Marie-Tooth disease, which are clinically and genetically heterogeneous. Züchner leads a large international collaborative effort called GEM.app involving over 450 investigators that has identified numerous genes for various neurodegenerative and neuromuscular disorders through shared exome and genome data.
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Genetics of Inherited Axonopathies
- 1. Stephan Züchner, MD, PhD Department of Human Genetics and Hussman Institute for Human Genomics University of Miami
- 2. Major developments have put human genetics on a new trajectory in recent years o Sequencing has improved >100,000 fold in the past 10 years. o Cost for an individual whole human genome is now ~$5,000. o Importantly, next year below $2,000 I.
- 3. II.
- 4. Excess of rare variants in human populations Tennessen et al. 2012 III. The number of rare variants growths unabated. Nelson, 2012
- 5. Our genome composition is tied to our (recent) history as a species • Todays heterogeneous Mendelian diseases arose in recent history. • It will be challenging to sort out true disease causing variants from high background of rare variation.
- 6. Inherited axonopathies • Inherited neurodegenerative diseases of long axons • Archetypical diseases include: • Hereditary Spastic Paraplegias • Hereditary Motor and Sensory Neuropathies (Charcot-Marie-Tooth disease) • Clinically heterogeneous and neurologically distinct (central vs peripheral), • but, these diseases share biology and genetics. • >120 known disease genes • 40 – 70% of patients without diagnosis
- 7. Functional candidate genes Whole exome/ genome sequencing Positional candidate genes via human genome project year CMT1A linkage studies JM Charcot, P Marie, HH Tooth 2014 CMT gene discovery Timmerman et al 2014
- 8. Neurodegenerative diseases show increasing genetic/ phenotypic/ mechanistic overlap Mitochondrial disease Mitochondrial disease Spastic Paraplegia Spastic Paraplegia ALSALS FTD/Deme ntia FTD/Deme ntia AtaxiaAtaxia Spinal muscular Atrophy Spinal muscular Atrophy Optic atrophy Optic atrophy AlzheimerAlzheimer Muscular Dystrophies Muscular Dystrophies Peripheral neuropathies Peripheral neuropathies
- 9. Interest in phenotyping Insight into overlap and heterogeneity of motoneuron diseases + + $$$ • We decided to sequence a large number of patients with such phenotypes • Convinced many colleagues to join in • CREATE • INC
- 10. • Interest in phenotyping • Insight into overlap and heterogeneity of motoneuron diseases + + $$$
- 11. The joys of working with “big data” … Typical next-generation sequencing analysis file (.VCF file)
- 12. •effectively managing larger exome and/or genome datasets, especially for smaller labs •direct hands-on analysis and contextual interpretation of variant data for many genomes •Combining data from small and medium-sized clinical and research- based teams around the world will significantly increase the opportunities for the entire community to identify new genes. Challenges that come with large scale genomic data
- 14. Gonzalez et al, 2013
- 15. • Invite collaborators • Create Shared Projects • Manage who can see what • Expand your own team • etc
- 16. >450 investigators 36 countries >5,000 exomes 90 phenotypes ~1,000 genomes GEM.app is used world-wide
- 17. Examples of diseases and participating groups • Mitochondrial disease community (UMDF/ MSeqDR) • Inherited Neuropathy Consortium (INC) • European epilepsy consortia • Hereditary spastic paraplegia network • Ataxia initiative • Amyotrophic Lateral Sclerosis group • Alzheimer disease, cardiomyopathy, rare and unique syndromes, deafness, motor neuron diseases, optic atrophy, ichthyosis, schizophrenia, …
- 18. 1. No sharing of data 2. Full mutual access to exomes/ genomes • anything from individual exomes to sets of cases and controls 3. Anonymous sharing of variants • Via genotype counts across entire GEM.app database • via a new ‘hit’ feature showing significant changes per gene and phenotype • on a gene-by gene basis in GVDHD (opt-in) Collaborative data mining
- 19. http://matchmakerexchange.org/ GEM.app is a key member of Matchmaker Exchange • Genomic sharing beyond a single database
- 20. WWOX Ataxia PNPLA6 Ataxia, CMT, BNS, HSP STAT5A Athrogryposis ARSG ATX GRP98 ATX SARM1 axonal protection SID-1 C.elegans SIX6 Congenital Blindness IGSF3 Congenital Nasolacrimal Duct Obstruction TEMXX Deafness NAGLU HSN SZT2 Intellectual Disability FAM183A Intellectual Disability ANKRD11 KBG syndrome DNAJC5 KUF PSEN1 KUF LIMS2 MYO SLITRK6 Myopia SYT2 Lambert-Eaton like ACTG2 Syndrome BICD2 SMA/CMT DNASE1L3 Vasculities AARS CMT HINT1 CMT HARS CMT PDK3 CMT MARS CMT2 C19ORF12 CMT SLC25A46 CMT2 optic atropy FXBO38 CMT2 JAG1 CMT2 TBCEL CMT2 MORC2 CMT2 TUBA8 CMT2 IGHMBP2 CMT2 ITSN2 CMT2 ZFP106 CMT2 VCP CMT2 RTN2 HSP CYP2U1 HSP DDHD1 HSP GBA2 HSP DDHD2 HSP B4GALNT1 HSP KIF1C HSP REEP2 HSP POLR3A HSP KPNA3 HSP
- 21. Example: BICD2 gene identification MAKING DATA DISCOVERABLE
- 22. BICD2 is associated with a set of diverse phenotype DCSMA Dominant congenital spinal muscular atrophy UMN Upper Motor Neuron disease
- 23. BICD2: Clinical impression and MRI signs Sparing of medial adductors and semitendinosus
- 24. • BICD2 is part of the dynein/dynactin complex • DYNC1H1 is also part of this complex --> shows very similar phenotype similar MRI findings BICD2 and DYNC1H1 act as molecular motors
- 25. Example: VCP gene identification Sizable CMT2 family with negative clinical testing results
- 26. Whole exome sequencing Severity prediction Value Range GERP score 6.07 -12.3 - 6.17 PhastCons 1 0 - 1 PolyPhen2 Probably damaging Benign, Possibly damaging, Probably damaging MutationTaster Disease causing Polymorphism - Disease causing MutationAssessor High Neutral, Low, Medium, High LRT Deleterious Unknown, Neutral, Deleterious SIFT Tolerated Tolerated - Damaging Disruption of autophagosome maturationComplete segregation in large family
- 27. The VCP protein is an important functional hub Gene-interaction analysis: Diseases caused by VCP: •1-2% of familial amyotrophic lateral sclerosis •inclusion body myopathy with Paget’s disease of the bone •frontotemporal dementia •hereditary spastic paraplegia Gonzalez et al, 2014 • BioGrid experimental interactions • Up to two intermediates • Flexible grid pulls interacting genes towards each other
- 28. Example: PNPLA6 gene identification
- 29. Boucher Neuhäuser Syndrome Gordon Holmes Syndrome Ataxia Hypogonadotrophic hypogonadism Chorioretinal dystrophy (Peripheral neuropathy) Ataxia Hypogonadotrophic hypogonadism Spasticity
- 30. Triad of Boucher Neuhäuser syndrome Hypogonadism Chorioretinal dystrophy Ataxia
- 31. The phenotype of PNPLA6 is broad J Med Genetics Neuropathy target esterase impairments cause Oliver–McFarlane and Laurence–Moon syndromes Triad of congenital trichomegaly, chorioretinal atrophy, and hypopituitarism. In our patients, thyroid and growth hormone replacement during childhood successfully improved the pituitary sequelae of intellectual disability and short stature. However, vision loss was progressive and devastating.
- 33. What is happening right now? • Unprecedented pace of gene discovery • In the coming decade the genotype/ phenotype relationships in motor neuron diseases will be defined in great detail • Inflationary value of new gene discovery What is the outlook? • It will get more difficult to identify sufficient genetic support for new genes (second family). • Still, we believe each of the classic phenotypes will contain several hundred genes in the end to explain >95%of patients. • Huge opportunity to define the biology through genetics (pathways).
- 34. o Hussman Institute for Human Genomics: faculty and especially Michael Gonzalez, Fiorella Speziani, Rafael Acosta, Mustafa Tekin, Gladys Montenegro, Eric Powel, William Hulme, Ioanna Konidari o The Inherited Neuropathies Consortium (INC); Mike Shy, Mary Reilly, Steve Scherer, David Herrmann, … o Rebecca Schule, Michael Benatar, Giovanni Stevanin, Ludger Schols, Peter de Jonghe, Garth Nicholson, Marina Kennerson, Manoj Menezes, Wilson Marques, Michaela Auer-Grumbach, Antonio Orlacchio, … o These studies were supported by the National Institute for Neurology and Stroke (R01NS065712, R01NS072248, R01NS075764, U54NS065712 to SZ), MDA, CMTA Miami Key Biscayne Coconut Grove
Editor's Notes
- In this figure you see all known genes and loci for hereditary neuropathies. The genes are marked in orange, and loci are highlighted in blue. Until now 17genes were identified, with many more surely to follow. This is in contras to the clinical homogeneity of the disease.
- even CMT receives not so muchpublic attention it is the most .... What turned out several years ago is that the disease is extremely genetically heterogeneous. Each disease is its own xperiment that tells us about the function of one aspect