BACKGROUND Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level. METHODS To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient’s clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes. RESULTS We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%). CONCLUSIONS Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children’s Hospital Foundation and others.)

BackgroundPhosphatidylinositol glycan biosynthesis class A protein (PIGA) is one of the enzymes involved in the biosynthesis of glycosylphosphatidylinositol (GPI) anchor proteins, which function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Until recently, only somatic PIGA mutations had been reported in patients with paroxysmal nocturnal hemoglobinuria (PNH), while germline mutations had not been observed, and were suspected to result in lethality. However, in just two years, whole exome sequencing (WES) analyses have identified germline PIGA mutations in male patients with XLIDD (X-linked intellectual developmental disorder) with a wide spectrum of clinical presentations.Methods and resultsHere, we report on a new missense PIGA germline mutation [g.15342986C>T (p.S330N)] identified via WES followed by Sanger sequencing, in a Chinese male infant presenting with developmental arrest, infantile spasms, a pattern of lesion distribution on brain MRI resembling that typical of maple syrup urine disease, contractures, dysmorphism, elevated alkaline phosphatase, mixed hearing loss (a combination of conductive and sensorineural), liver dysfunction, mitochondrial complex I and V deficiency, and therapy-responsive dyslipidemia with confirmed lipoprotein lipase deficiency. X-inactivation studies showed skewing in the clinically unaffected carrier mother, and CD109 surface expression in patient fibroblasts was 57% of that measured in controls; together these data support pathogenicity of this mutation. Furthermore, we review all reported germline PIGA mutations (1 nonsense, 1 frameshift, 1 in-frame deletion, five missense) in 8 unrelated families.ConclusionsOur case further delineates the heterogeneous phenotype of this condition for which we propose the term ‘PIGA deficiency’. While the phenotypic spectrum is wide, it could be classified into two types (severe and less severe) with shared hallmarks of infantile spasms with hypsarrhythmia on EEG and profound XLIDD. In severe PIGA deficiency, as described in our patient, patients also present with dysmorphic facial features, multiple CNS abnormalities, such as thin corpus callosum and delayed myelination, as well as hypotonia and elevated alkaline phosphatase along with liver, renal, and cardiac involvement; its course is often fatal. The less severe form of PIGA deficiency does not involve facial dysmorphism and multiple CNS abnormalities; instead, patients present with milder IDD, treatable seizures and generally a longer lifespan.

Although inborn errors of metabolism do not represent the most common cause of seizures, their early identification is of utmost importance, since many will require therapeutic measures beyond that of common anti-epileptic drugs, either in order to control seizures, or to decrease the risk of neurodegeneration. We translate the currently-known literature on metabolic etiologies of epilepsy (268 inborn errors of metabolism belonging to 21 categories, with 74 treatable errors), into a 2-tiered diagnostic algorithm, with the first-tier comprising accessible, affordable, and less invasive screening tests in urine and blood, with the potential to identify the majority of treatable conditions, while the second-tier tests are ordered based on individual clinical signs and symptoms. This resource aims to support the pediatrician, neurologist, biochemical, and clinical geneticists in early identification of treatable inborn errors of metabolism in a child with seizures, allowing for timely initiation of targeted therapy with the potential to improve outcomes.

PEHO syndrome (OMIM no. 260565) is characterized by myoclonic jerking and infantile spasms, profound psychomotor retardation with the absence of motor milestones and speech, absence or early loss of visual fixation with atrophy of optic discs by 2 years of age and progressive brain atrophy on neuroimaging. We describe the results of a genomic study of a girl with PEHO syndrome and review the literature on cases with a disease-causing variant in the same gene. Exome sequencing of the index and unaffected parents followed by Sanger confirmation identified nine candidate genes harboring nonsynonymous rare variants identified by trio whole-exome sequencing. The de novo variant, a missense variant (c.296C4T, p.(T99M)), affecting the motor domain of KIF1A was considered the pathogenic mutation. The literature review revealed 24 cases with disease-causing variants in the motor domain of KIF1A, of which three met all the criteria for PEHO syndrome and an additional patient with incomplete clinical data met four of the five criteria. If the criteria were modified to include cases with any convulsive disorder and less profound intellectual disability, a total of six patients met all five of the criteria, three patients met four of the criteria and six met three of the criteria. Our results indicate that the molecular basis for PEHO syndrome, in at least a subset of patients, is a dominant KIF1A variant affecting the motor domain of the protein. Variable expressivity is seen with recurrent variants causing the full phenotype of PEHO syndrome in some patients and in other patients, a partial or milder PEHO phenotype.

BackgroundFatty acid amide hydrolase 2 (FAAH2) is a hydrolase that mediates the degradation of endocannabinoids in man. Alterations in the endocannabinoid system are associated with a wide variety of neurologic and psychiatric conditions, but the phenotype and biochemical characterization of patients with genetic defects of FAAH2 activity have not previously been described. We report a male with autistic features with an onset before the age of 2 years who subsequently developed additional features including anxiety, pseudoseizures, ataxia, supranuclear gaze palsy, and isolated learning disabilities but was otherwise cognitively intact as an adult.Methods and resultsWhole exome sequencing identified a rare missense mutation in FAAH2, hg19: g.57475100G > T (c.1372G > T) resulting in an amino acid change (p.Ala458Ser), which was Sanger confirmed as maternally inherited and absent in his healthy brother. Alterations in lipid metabolism with abnormalities of the whole blood acyl carnitine profile were found. Biochemical and molecular modeling studies confirmed that the p.Ala458Ser mutation results in partial inactivation of FAAH2. Studies in patient derived fibroblasts confirmed a defect in FAAH2 activity resulting in altered levels of endocannabinoid metabolites.ConclusionsWe propose that genetic alterations in FAAH2 activity contribute to neurologic and psychiatric disorders in humans.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0248-3) contains supplementary material, which is available to authorized users.

Tangier disease is a rare, autosomal recessive disorder caused by mutations in the ABCA1 gene and is characterized by near absence of plasma high-density lipoprotein cholesterol, accumulation of cholesterol in multiple tissues, peripheral neuropathy, and accelerated atherosclerosis. Here we report three new kindreds with Tangier disease harboring both known and novel mutations in ABCA1. One patient was identified to be homozygous for a nonsense mutation, p.Gln1038*. In a remarkably large Tangier disease pedigree with four affected siblings, we identified compound heterozygosity for previously reported missense variants, p.Arg937Val and p.Thr940Met, and show that both of these mutations result in significantly impaired cholesterol efflux in transfected cells. In a third pedigree, the proband was identified to be compound heterozygous for two novel mutations, a frameshift (p.Ile1200Hisfs*4) and an intronic variant (c.4176-11T>G), that lead to the creation of a cryptic splice site acceptor and premature truncation, p.Ser1392Argfs*6. We demonstrate that this mutation arose de novo, the first demonstration of a pathogenic de novo mutation in ABCA1 associated with Tangier disease. We also report results of glucose tolerance testing in a Tangier disease kindred for the first time, showing a gene-dose relationship between ABCA1 activity and glucose tolerance and suggesting that Tangier disease patients may have substantially impaired islet function. Our findings provide insight into the diverse phenotypic manifestations of this rare disorder, expand the list of pathogenic mutations in ABCA1, and increase our understanding of how specific mutations in this gene lead to abnormal cellular and physiological phenotypes.

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Primary 5-oxoprolinuria (pyroglutamic aciduria) is caused by a genetic defect in the γ-glutamyl cycle, affecting either glutathione synthetase or 5-oxoprolinase. While several dozens of patients with glutathione synthetase deficiency have been reported, with hemolytic anemia representing the clinical key feature, 5-oxoprolinase deficiency due to OPLAH mutations is less frequent and so far has not attracted much attention. This has prompted us to investigate the clinical phenotype as well as the underlying genotype in patients from 14 families of various ethnic backgrounds who underwent diagnostic mutation analysis following the detection of 5-oxoprolinuria. In all patients with 5-oxoprolinuria studied, bi-allelic mutations in OPLAH were indicated. An autosomal recessive mode of inheritance for 5-oxoprolinase deficiency is further supported by the identification of a single mutation in all 9/14 parent sample sets investigated (except for the father of one patient whose result suggests homozygosity), and the absence of 5-oxoprolinuria in all tested heterozygotes. It is remarkable, that all 20 mutations identified were novel and private to the respective families. Clinical features were highly variable and in several sib pairs, did not segregate with 5-oxoprolinuria. Although a pathogenic role of 5-oxoprolinase deficiency remains possible, this is not supported by our findings. Additional patient ascertainment and long-term follow-up is needed to establish the benign nature of this inborn error of metabolism. It is important that all symptomatic patients with persistently elevated levels of 5-oxoproline and no obvious explanation are investigated for the genetic etiology.