Unique bioinformatic approach and comprehensive reanalysis improve diagnostic yield of clinical exomes.

Clinical exome sequencing (CES) is increasingly being utilized; however, a large proportion of patients remain undiagnosed, creating a need for a systematic approach to increase the diagnostic yield. We have reanalyzed CES data for a clinically heterogeneous cohort of 102 probands with likely Mendelian conditions, including 74 negative cases and 28 cases with candidate variants, but reanalysis requested by clinicians. Reanalysis was performed by an interdisciplinary team using a validated custom-built pipeline, "Variant Explorer Pipeline" (VExP).

Revising the Psychiatric Phenotype of Homocystinuria.

Purpose: Associations of psychiatric and psychological symptoms with homocystinuria (HCU) have been described in multiple reports. This retrospective study was undertaken to refine the psychological phenotype among HCU patients and identify biomedical markers that could be used for prediction of those psychiatric or psychological symptoms.

Methods: This study examines the prevalence of psychological symptoms within a sample of 25 patients with classical homocystinuria.

Expanding the phenotypic spectrum associated with OPHN1 variants.

Genomic sequencing has allowed for the characterization of new gene-to-disease relationships, as well as the identification of variants in established disease genes in patients who do not fit the classically-described phenotype. This is especially true in rare syndromes where the clinical spectrum is not fully known. After a lengthy and costly diagnostic odyssey, patients with atypical presentations may be left with many questions even after a genetic diagnosis is identified.

Utility of Genetic Testing in Fetal Alcohol Spectrum Disorder.

Objective: To study the utility of genetic evaluation and testing in patients with suspected fetal alcohol spectrum disorder (FASD).

Study Design: We performed a retrospective chart review of all patients (n = 36) referred for evaluation for suspected FASD to the genetics clinic at Boston Children's Hospital between January 2006 and January 2013. Records of all patients were reviewed to obtain the medical history, family history, examination findings, and investigations, including genetic testing.

Review of Salient Investigational Drugs for the Treatment of Fragile X Syndrome.

Objectives: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability, in addition to being the commonest diagnosable cause of autism. The identification of the biochemical mechanism underlying this disorder has provided amenable targets for therapy. This review aims to provide an overview of investigational drug therapies for FXS.

Expanding the phenotypic spectrum of GABRG2 variants: a recurrent GABRG2 missense variant associated with a severe phenotype.

Pathogenic missense and truncating variants in the GABRG2 gene cause a spectrum of epilepsies, from Dravet syndrome to milder simple febrile seizures. In most cases, pathogenic missense variants in the GABRG2 gene segregate with a febrile seizure phenotype. In this case series, we report a recurrent, de novo missense variant (c0.

A novel neurodevelopmental disorder associated with compound heterozygous variants in the huntingtin gene.

We report compound heterozygous variants in HTT, the gene encoding huntingtin, in association with an autosomal recessive neurodevelopmental disorder. Three siblings presented with severe global developmental delay since birth, central hypotonia progressing to spastic quadraparesis, feeding difficulties, dystonia (2/3 sibs), prominent midline stereotypies (2/3), bruxism (1/3), high myopia (2/3), and epilepsy (1/3). Whole exome sequencing identified compound heterozygous variants in HTT that co-segregated in the three affected sibs and were absent in an unaffected sib.

De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.

Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published.

New innovations: therapeutic opportunities for intellectual disabilities.

Intellectual disability is common and is associated with significant morbidity. Until the latter half of the 20th century, there were no efficacious treatments. Following initial breakthroughs associated with newborn screening and metabolic corrections, little progress was made until recently.

Glutamate carboxypeptidase II and folate deficiencies result in reciprocal protection against cognitive and social deficits in mice: implications for neurodevelopmental disorders.

Interactions between genetic and environmental risk factors underlie a number of neuropsychiatric disorders, including schizophrenia (SZ) and autism (AD). Due to the complexity and multitude of the genetic and environmental factors attributed to these disorders, recent research strategies focus on elucidating the common molecular pathways through which these multiple risk factors may function. In this study, we examine the combined effects of a haplo-insufficiency of glutamate carboxypeptidase II (GCPII) and dietary folic acid deficiency.

Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.

Research has implicated mutations in the gene for neurexin-1 (NRXN1) in a variety of conditions including autism, schizophrenia, and nicotine dependence. To our knowledge, there have been no published reports describing the breadth of the phenotype associated with mutations in NRXN1. We present a medical record review of subjects with deletions involving exonic sequences of NRXN1.

Phenotypic characterization of mice heterozygous for a null mutation of glutamate carboxypeptidase II.

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. Disturbed glutamate signaling resulting in hypofunction of N-methyl-D-aspartate receptors (NMDAR) has been implicated in the pathophysiology of schizophrenia. Glutamate Carboxypeptidase II (GCP II) hydrolyzes N-acetyl-alpha L-aspartyl-L-glutamate (NAAG) into glutamate and N-acetyl-aspartate.

An altered neonatal behavioral phenotype in Mecp2 mutant mice.

We examined somatic growth, somatosensory reflexes, and ultrasonic calls from postnatal day 3 to day 18 in Mecp2 mutant mice, a mouse model of Rett syndrome. Both Mecp2 null male and Mecp2 heterozygous female mice exhibited normal somatic growth, but transient delays in the development of some reflexes relative to sex-matched wild-type mice. Both Mecp2 null male and heterozygous female mice exhibited dramatic increases in ultrasonic vocalizations in response to social isolation; these differences were evident as early as postnatal day 5.

Do maternal folate and homocysteine levels play a role in neurodevelopmental processes that increase risk for schizophrenia?

Objective: Evidence from many different lines of research supports the hypothesis that schizophrenia is a disorder of development with etiological factors implicated as early as the second trimester in utero. We suggest that low maternal folate, acting to increase homocysteine levels, may provide a functional link between many of the identified prenatal risk factors and the hypothesized mechanisms whereby neurodevelopmental patterning deviates toward a schizophrenic potential.

Methods: PubMed was searched from the present back to 1963, when elevated homocysteine was identified as a pathogen in homocystinuria as first described by Carson and colleagues (Arch Dis Child 1963;38:425-36).

Arginase deficiency with lethal neonatal expression: evidence for the glutamine hypothesis of cerebral edema.

We describe a rare and lethal case of arginase deficiency in a 2-day-old female infant with encephalopathy and cerebral edema. The levels of glutamine and arginine but not ammonia were markedly elevated, lending support to the "glutamine hypothesis" as the mechanism of cerebral edema in urea cycle defects.