Role of reverse phenotyping in interpretation of next generation sequencing data and a review of INPP5E related disorders

Goede, Christian de; Yue, Wyatt W.; Yan, Guanhua; Ariyaratnam, Shyamala; Chandler, Kate; Downes, Laura; Khan, Nasaim; Mohan, Meyyammai; Lowe, Martin; Banka, Siddharth

doi:10.1016/j.ejpn.2015.11.012

Cited by 37 publications

(48 citation statements)

References 13 publications

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“…Where required, reverse phenotyping was performed. 23 Available brain imaging and EEG data were reviewed for all participants. Epilepsy syndromes and seizure types were classified according to the International League Against Epilepsy (ILAE) classification criteria.…”

Section: Study Participantsmentioning

confidence: 99%

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Study

2018

The American Journal of Human Genetics

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Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the a 1-subunit of the voltage-gated Ca V 2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca V 2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

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Section: Study Participantsmentioning

confidence: 99%

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Study

2018

The American Journal of Human Genetics

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“…Both BCAT2 variants were confirmed by Sanger sequencing using standard methods (Figure B). Biochemical phenotyping revealed elevated valine, leucine, and isoleucine concentrations in plasma (Table ) (Supplementary Methods).…”

Section: Methods and Resultsmentioning

confidence: 99%

“…Both BCAT2 variants were confirmed by Sanger sequencing using standard methods ( Figure 1B). Biochemical phenotyping 15 revealed elevated valine, leucine, and isoleucine concentrations in plasma ( Subject 2, an 11-year-old girl, was one of two children born to consanguineous parents of Pakistani ancestry and presented at the age of 2 years with global developmental delay and microcephaly. She was diagnosed with learning difficulties and ataxia along with signs of spastic paraparesis.…”

Section: Methods and Resultsmentioning

confidence: 99%

Expanding the genetic and phenotypic spectrum of branched‐chain amino acid transferase 2 deficiency

knerr

Colombo

Urquhart

et al. 2019

J of Inher Metab Disea

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The first step in branched‐chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transferase isoenzymes, cytoplasmic branched‐chain amino acid transferase (BCAT) 1, and mitochondrial BCAT2. Defects in the second step of BCAA catabolism cause maple syrup urine disease (MSUD), a condition which has been far more extensively investigated. Here, we studied the consequences of BCAT2 deficiency, an ultra‐rare condition in humans. We present genetic, clinical, and functional data in five individuals from four different families with homozygous or compound heterozygous BCAT2 mutations which were all detected following abnormal biochemical profile results or familial mutation segregation studies. We demonstrate that BCAT2 deficiency has a recognizable biochemical profile with raised plasma BCAAs and, in contrast with MSUD, low‐normal branched‐chain keto acids (BCKAs) with undetectable l‐allo‐isoleucine. Interestingly, unlike in MSUD, none of the individuals with BCAT2 deficiency developed acute encephalopathy even with exceptionally high BCAA levels. We observed wide‐ranging clinical phenotypes in individuals with BCAT2 deficiency. While one adult was apparently asymptomatic, three individuals had presented with developmental delay and autistic features. We show that the biochemical characteristics of BCAT2 deficiency may be amenable to protein‐restricted diet and that early treatment may improve outcome in affected individuals. BCAT2 deficiency is an inborn error of BCAA catabolism. At present, it is unclear whether developmental delay and autism are parts of the variable phenotypic spectrum of this condition or coincidental. Further studies will be required to explore this.

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“… 33 In another study, Goede et al , after a detailed clinical evaluation of two families referred for global developmental delay and learning disability, have excluded that the presumptive causative missense variant RABL6 is the underlying cause of the disorder and have instead demonstrated that the condition is because of a homozygous INPP5E mutation. 34 Reverse phenotyping, together with careful protein structural analysis and functional tests, had a crucial role in achieving the correct diagnosis. Further in-depth study of the mutational and phenotypic spectra associated with INPP5E has demonstrated that mutations in this gene lead to a range of ciliopathy-phenotypes with considerable intra-familial phenotypic variability.…”

Section: Reverse Phenotyping Of Psychiatric Phenotypesmentioning

confidence: 99%

Genetic tests in major psychiatric disorders—integrating molecular medicine with clinical psychiatry—why is it so difficult?

Demkow

Wolańczyk

2017

Transl Psychiatry

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With the advent of post-genomic era, new technologies create extraordinary possibilities for diagnostics and personalized therapy, transforming todays’ medicine. Rooted in both medical genetics and clinical psychiatry, the paper is designed as an integrated source of information of the current and potential future application of emerging genomic technologies as diagnostic tools in psychiatry, moving beyond the classical concept of patient approach. Selected approaches are presented, starting from currently used technologies (next-generation sequencing (NGS) and microarrays), followed by newer options (reverse phenotyping). Next, we describe an old concept in a new light (endophenotypes), subsequently coming up with a sophisticated and complex approach (gene networks) ending by a nascent field (computational psychiatry). The challenges and barriers that exist to translate genomic research to real-world patient assessment are further discussed. We emphasize the view that only a paradigm shift can bring a fundamental change in psychiatric practice, allowing to disentangle the intricacies of mental diseases. All the diagnostic methods, as described, are directed at uncovering the integrity of the system including many types of relations within a complex structure. The integrative system approach offers new opportunity to connect genetic background with specific diseases entities, or concurrently, with symptoms regardless of a diagnosis. To advance the field, we propose concerted cross-disciplinary effort to provide a diagnostic platform operating at the general level of genetic pathogenesis of complex-trait psychiatric disorders rather than at the individual level of a specific disease.

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Role of reverse phenotyping in interpretation of next generation sequencing data and a review of INPP5E related disorders

Cited by 37 publications

References 13 publications

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Expanding the genetic and phenotypic spectrum of branched‐chain amino acid transferase 2 deficiency

Genetic tests in major psychiatric disorders—integrating molecular medicine with clinical psychiatry—why is it so difficult?

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