Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands

Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation: The Deciphering Developmental Disorders Study

Individuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,293 families with individuals with DDs, and meta-analysed these data with published data on 3,287 individuals with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the affected individual, the relatedness of their parents and the age of both father and mother. We identified 94 genes enriched for damaging de novo mutation at genome-wide significance (P < 7 × 10−7), including 14 genes for which compelling data for causation was previously lacking. We have characterised the phenotypic diversity among these genetic disorders. We demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42% of our cohort carry pathogenic DNMs (single nucleotide variants and indels) in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder resulting in altered-function (e.g. activating, dominant negative). We established that most haplo insufficient developmental disorders have already been identified, but that many altered-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that developmental disorders caused by DNMs have an average birth prevalence of 1 in 213 to 1 in 448 (0.22-0.47% of live births), depending on parental age

Large-scale discovery of novel genetic causes of developmental disorders

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders1, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach2 to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing3,4,5,6,7,8,9,10,11 and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders

Anxious, hypoactive phenotype combined with motor deficits in Gtf2ird1 null mouse model relevant to Williams syndrome

Williams–Beuren syndrome (WBS) is a rare genetic disorder caused by a hemizygous deletion of around 28 genes on the long arm of chromosome 7 (7q11.23), characterized by a unique spectrum of behavioral impairments, including mental retardation, deficits in visuospatial constructive cognition, hypersociability, anxiety and simple phobias. Physical characteristics include dysmorphic faces, short stature, oculomotor deficits, gross and fine coordination impairments, diminished control of balance and mild extrapyramidal signs as well as gait abnormalities resembling gait hypokinesia. Genes near the distal deletion breakpoint appear to contribute most to the WBS cognitive and behavioral profile and include the GTF family of transcription factors: GTF2I, GTF2IRD1, GTF2IRD2. We have previously shown that heterozygous deletions of GTF2IRD1 in humans and homozygous deletion in mice contributes to craniofacial abnormalities. Here we show an important role of this gene in motor coordination and anxiety ascertained from extensive behavioral mouse phenotyping. Gtf2ird1 null mice showed lower body weight, decreased spontaneous and circadian locomotor activity, diminished motor coordination and strength, gait abnormalities, increased anxiety and an elevated endocrinological response to stress. Gtf2ird1 heterozygous mice displayed lower body weight and decreased circadian activity, but only minor motor coordination and anxiety-related behavioral dysfunctions. Our study strongly supports a role for GTF2IRD1 in the motoric and anxiety-related abnormalities seen in Williams–Beuren syndrome, and suggests basal ganglia and potentially cerebellar abnormalities in Gtf2ird1 mice

Safety and efficacy of pridopidine in patients with Huntington\u27s disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study

© 2019 Elsevier Ltd Background: Previous trials have shown that pridopidine might reduce motor impairment in patients with Huntington\u27s disease. The aim of this study was to ascertain whether higher doses of pridopidine than previously tested reduce motor symptoms in a dose-dependent manner while maintaining acceptable safety and tolerability. Methods: PRIDE-HD was a randomised, placebo-controlled, phase 2, dose-ranging study in adults (aged ≥21 years) with Huntington\u27s disease at outpatient clinics in 53 sites across 12 countries (Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, the Netherlands, the UK, and the USA). Eligible patients had clinical onset after age 18 years, 36 or more cytosine-adenine-guanine repeats in the huntingtin gene, motor symptoms (Unified Huntington\u27s Disease Rating Scale total motor score [UHDRS-TMS] ≥25 points), and reduced independence (UHDRS independence score ≤90%). Patients were randomly assigned (1:1:1:1:1) with centralised interactive-response technology to receive one of four doses of pridopidine (45, 67·5, 90, or 112·5 mg) or placebo orally twice a day for 52 weeks. Randomisation was stratified within centres by neuroleptic drug use. The primary efficacy endpoint was change in the UHDRS-TMS from baseline to 26 weeks, which was assessed in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment (full analysis set). Participants and investigators were masked to treatment assignment. This trial is registered with EudraCT (2013-001888-23) and ClinicalTrials.gov (NCT02006472). Findings: Between Feb 13, 2014, and July 5, 2016, 408 patients were enrolled and randomly assigned to receive placebo (n=82) or pridopidine 45 mg (n=81), 67·5 mg (n=82), 90 mg (n=81), or 112·5 mg (n=82) twice daily for 26 weeks. The full analysis set included 397 patients (81 in the placebo group, 75 in the 45 mg group, 79 in the 67·5 mg group, 81 in the 90 mg group, and 81 in the 112·5 mg group). Pridopidine did not significantly change the UHDRS-TMS at 26 weeks compared with placebo at any dose. The most frequent adverse events across all groups were diarrhoea, vomiting, nasopharyngitis, falls, headache, insomnia, and anxiety. The most common treatment-related adverse events were insomnia, diarrhoea, nausea, and dizziness. Serious adverse events occurred in the pridopidine groups only and were most frequently falls (n=5), suicide attempt (n=4), suicidal ideation (n=3), head injury (n=3), and aspiration pneumonia (n=3). No new safety or tolerability concerns emerged in this study. One death in the pridopidine 112·5 mg group due to aspiration pneumonia was considered to be possibly related to the study drug. Interpretation: Pridopidine did not improve the UHDRS-TMS at week 26 compared with placebo and, thus, the results of secondary or tertiary analyses in previous trials were not replicated. A potentially strong placebo effect needs to be ruled out in future studies. Funding: Teva Pharmaceutical Industries

Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study

Background: Previous trials have shown that pridopidine might reduce motor impairment in patients with Huntington's disease. The aim of this study was to ascertain whether higher doses of pridopidine than previously tested reduce motor symptoms in a dose-dependent manner while maintaining acceptable safety and tolerability. Methods: PRIDE-HD was a randomised, placebo-controlled, phase 2, dose-ranging study in adults (aged ≥21 years) with Huntington's disease at outpatient clinics in 53 sites across 12 countries (Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, the Netherlands, the UK, and the USA). Eligible patients had clinical onset after age 18 years, 36 or more cytosine-adenine-guanine repeats in the huntingtin gene, motor symptoms (Unified Huntington's Disease Rating Scale total motor score [UHDRS-TMS] ≥25 points), and reduced independence (UHDRS independence score ≤90%). Patients were randomly assigned (1:1:1:1:1) with centralised interactive-response technology to receive one of four doses of pridopidine (45, 67·5, 90, or 112·5 mg) or placebo orally twice a day for 52 weeks. Randomisation was stratified within centres by neuroleptic drug use. The primary efficacy endpoint was change in the UHDRS-TMS from baseline to 26 weeks, which was assessed in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment (full analysis set). Participants and investigators were masked to treatment assignment. This trial is registered with EudraCT (2013-001888-23) and ClinicalTrials.gov (NCT02006472). Findings: Between Feb 13, 2014, and July 5, 2016, 408 patients were enrolled and randomly assigned to receive placebo (n=82) or pridopidine 45 mg (n=81), 67·5 mg (n=82), 90 mg (n=81), or 112·5 mg (n=82) twice daily for 26 weeks. The full analysis set included 397 patients (81 in the placebo group, 75 in the 45 mg group, 79 in the 67·5 mg group, 81 in the 90 mg group, and 81 in the 112·5 mg group). Pridopidine did not significantly change the UHDRS-TMS at 26 weeks compared with placebo at any dose. The most frequent adverse events across all groups were diarrhoea, vomiting, nasopharyngitis, falls, headache, insomnia, and anxiety. The most common treatment-related adverse events were insomnia, diarrhoea, nausea, and dizziness. Serious adverse events occurred in the pridopidine groups only and were most frequently falls (n=5), suicide attempt (n=4), suicidal ideation (n=3), head injury (n=3), and aspiration pneumonia (n=3). No new safety or tolerability concerns emerged in this study. One death in the pridopidine 112·5 mg group due to aspiration pneumonia was considered to be possibly related to the study drug. Interpretation: Pridopidine did not improve the UHDRS-TMS at week 26 compared with placebo and, thus, the results of secondary or tertiary analyses in previous trials were not replicated. A potentially strong placebo effect needs to be ruled out in future studies. Funding: Teva Pharmaceutical Industries

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities