Phenotypic Spectrum in a Family Sharing a Heterozygous Variant.

Background And Purpose: Mutations in have classically been associated with benign familial neonatal and infantile seizures and more recently identified in patients with neurodevelopmental disorders and abnormal electroencephalogram (EEG) findings. We present 4 affected patients from a family with a pathogenic mutation in with a unique constellation of clinical findings.

Methods: A family of 3 affected siblings and mother sharing a pathogenic variant are described, including clinical history, genetic results, and EEG and magnetic resonance imaging (MRI) findings.

CNTN6 copy number variations: Uncertain clinical significance in individuals with neurodevelopmental disorders.

Copy number variations (CNVs) of the CNTN6 gene - a member of the contactin gene superfamily - have been previously proposed to have an association with neurodevelopmental and autism spectrum disorders. However, no functional evidence has been provided to date and phenotypically normal and mildly affected carriers complicate the interpretation of this aberration. In view of conflicting reports on the pathogenicity of CNVs involving CNTN6 and association with different phenotypes, we, independently, evaluated clinical features of nineteen patients with detected CNV of CNTN6 as part of their clinical microarray analysis at Children's Mercy and Nationwide Children's Hospitals for the period of 2008-2015.

Testing genetic modifiers of behavior and response to atomoxetine in autism spectrum disorder with ADHD.

Background: Frequent non-pathogenic genetic variants may act as moderators of phenotypic severity for complex disorders such as autism spectrum disorder (ASD). We previously identified polymorphisms affecting mRNA expression of candidate genes, including tryptophan hydroxylase 2 (), dopamine beta hydroxylase (), and dopamine transporter ().

Method: We compare genotypes and (1) clinical response to atomoxetine, (2) scores from the Autism Diagnostic Interview-Revised (ADI-R), and (3) severity of Attention Deficit Hyperactivity Disorder (ADHD) symptoms in a cohort of patients with ASD from multiple study sites.

Language Regression in an Atypical SLC6A1 Mutation.

Recent technological advances in exome sequencing or targeted gene sequencing with epilepsy panels have allowed clinicians to better understand the pathogenesis and clinical presentation of children with epilepsy. We present a child with a SLC6A1 mutation with language delay and autistic spectrum disorder and remind the reader that the identification of specific mutations in these conditions increase the likelihood of identification of potential therapeutic targets.

Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery.

Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID).

Human CRMP4 mutation and disrupted Crmp4 expression in mice are associated with ASD characteristics and sexual dimorphism.

Autism spectrum disorders (ASD) are more common among boys than girls. The mechanisms responsible for ASD symptoms and their sex differences remain mostly unclear. We previously identified collapsin response mediator protein 4 (CRMP4) as a protein exhibiting sex-different expression during sexual differentiation of the hypothalamic sexually dimorphic nucleus.

A retrospective chart review of the features of PTEN hamartoma tumour syndrome in children.

Objective: It is recognised that 5% - 10 % of children with macrocephaly and autism spectrum disorder (ASD) and/or intellectual disability (ID) have a heterozygous pathogenic mutation in the tumour suppressor gene that is associated with PTEN hamartoma tumour syndrome. However, the clinical features and course in children with a pathogenic mutation are unclear and have not been well documented.

Study Objectives: We undertook a retrospective chart review of children (< 18  years) with pathogenic mutations to ascertain clinical findings, clinical course and possible outcomes.

Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research.

Genome sequencing has revolutionized the diagnosis of genetic diseases. Close collaborations between basic scientists and clinical genomicists are now needed to link genetic variants with disease causation. To facilitate such collaborations, we recommend prioritizing clinically relevant genes for functional studies, developing reference variant-phenotype databases, adopting phenotype description standards, and promoting data sharing.

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.

Disclaimer: These recommendations are designed primarily as an educational resource for medical geneticists and other healthcare providers to help them provide quality medical services. Adherence to these recommendations is completely voluntary and does not necessarily assure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results.

Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR.

Meiosis-activating sterols (MAS) are substrates of SC4MOL and NSDHL in the cholesterol pathway and are important for normal organismal development. Oncogenic transformation by epidermal growth factor receptor (EGFR) or RAS increases the demand for cholesterol, suggesting a possibility for metabolic interference. To test this idea in vivo, we ablated Nsdhl in adult keratinocytes expressing KRAS(G12D).

Analysis of hedgehog signaling in cerebellar granule cell precursors in a conditional Nsdhl allele demonstrates an essential role for cholesterol in postnatal CNS development.

NSDHL is a 3β-hydroxysterol dehydrogenase that is involved in the removal of two C-4 methyl groups in one of the later steps of cholesterol biosynthesis. Mutations in the gene encoding the enzyme are responsible for the X-linked, male lethal mouse mutations bare patches and striated, as well as most cases of human CHILD syndrome. Rare, hypomorphic NSDHL mutations are also associated with X-linked intellectual disability in males with CK syndrome.

Reporting genomic secondary findings: ACMG members weigh in.

Purpose: The aim of this study was to survey American College of Medical Genetics and Genomics members about secondary findings from clinical genome-scale sequencing.

Methods: A Web-based survey was mailed to 1,687 members of the American College of Medical Genetics and Genomics. Exploratory factor analysis identified underlying factors assessed by survey items.

ERCC6 dysfunction presenting as progressive neurological decline with brain hypomyelination.

Mutations in ERCC6 are associated with growth failure, intellectual disability, neurological dysfunction and deterioration, premature aging, and photosensitivity. We describe siblings with biallelic ERCC6 mutations (NM_000124.2:c.

Family-based clinical associations and functional characterization of the serotonin 2A receptor gene (HTR2A) in autism spectrum disorder.

The serotonin 2A receptor gene (HTR2A) harbors two functional single nucleotide polymorphisms (SNPs) that are frequent in populations of African and European descent; rs6311, which affects mRNA expression, and rs6314, which changes the amino acid sequence of the encoded protein and affects the signaling properties of the receptor. Multiple clinical associations support a role for these SNPs in cognitive and neuropsychiatric phenotypes, although studies in autism spectrum disorder (ASD) remain equivocal. Here, we tested transmission disequilibrium of rs6311 and rs6314 in a cohort of 158 ASD trios (simplex and multiplex), observing significant under-transmission of the minor "A" allele of rs6311 to offspring with ASD (permuted P = 0.

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge.

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors.

Analysis of two candidate genes for Basan syndrome.

Basan syndrome is an extremely rare ectodermal dysplasia with autosomal dominant inheritance and variable expressivity. The etiology of Basan syndrome remains unknown. To identify the Basan syndrome gene, we sequenced keratin 14 (KRT14) and SMARCAD1 in a previously unreported kindred with the disease.

Targeting C4-demethylating genes in the cholesterol pathway sensitizes cancer cells to EGF receptor inhibitors via increased EGF receptor degradation.

Unlabelled: Persistent signaling by the oncogenic EGF receptor (EGFR) is a major source of cancer resistance to EGFR targeting. We established that inactivation of 2 sterol biosynthesis pathway genes, SC4MOL (sterol C4-methyl oxidase-like) and its partner, NSDHL (NADP-dependent steroid dehydrogenase-like), sensitized tumor cells to EGFR inhibitors. Bioinformatics modeling of interactions for the sterol pathway genes in eukaryotes allowed us to hypothesize and then extensively validate an unexpected role for SC4MOL and NSDHL in controlling the signaling, vesicular trafficking, and degradation of EGFR and its dimerization partners, ERBB2 and ERBB3.

Disorders of sterol synthesis: beyond Smith-Lemli-Opitz syndrome.

Since the discovery in 1993 that Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol biosynthesis, human disorders associated with additional enzymes involved in the conversion of lanosterol to cholesterol have been identified. This review will focus primarily on the clinical aspects of these disorders, highlighting newly described syndromes, such as SC4MOL deficiency and CK syndrome. We will also provide clinical descriptions of additional cases for extremely rare disorders, such as desmosterolosis.

Microdeletion 9q22.3 syndrome includes metopic craniosynostosis, hydrocephalus, macrosomia, and developmental delay.

Basal cell nevus syndrome (BCNS), also known as Gorlin syndrome (OMIM #109400) is a well-described rare autosomal dominant condition due to haploinsufficiency of PTCH1. With the availability of comparative genomic hybridization arrays, increasing numbers of individuals with microdeletions involving this locus are being identified. We present 10 previously unreported individuals with 9q22.