Ectodermal dysplasias: Classification and organization by phenotype, genotype and molecular pathway

An international advisory group met at the National Institutes of Health in Bethesda, Maryland in 2017, to discuss a new classification system for the ectodermal dysplasias (EDs) that would integrate both clinical and molecular information. We propose the following, a working definition of the EDs building on previous classification systems and incorporating current approaches to diagnosis: EDs are genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. Genetic variations in genes known to be associated with EDs that affect only one derivative of the ectoderm (attenuated phenotype) will be grouped as non‐syndromic traits of the causative gene (e.g., non‐syndromic hypodontia or missing teeth associated with pathogenic variants of EDA “ectodysplasin”). Information for categorization and cataloging includes the phenotypic features, Online Mendelian Inheritance in Man number, mode of inheritance, genetic alteration, major developmental pathways involved (e.g., EDA, WNT “wingless‐type,” TP63 “tumor protein p63”) or the components of complex molecular structures (e.g., connexins, keratins, cadherins)

Full-length Isoform Sequencing for Resolving the Molecular Basis of Charcot-Marie-Tooth 2A.

OBJECTIVES: Transcript sequencing of patient-derived samples has been shown to improve the diagnostic yield for solving cases of suspected Mendelian conditions, yet the added benefit of full-length long-read transcript sequencing is largely unexplored. METHODS: We applied short-read and full-length transcript sequencing and mitochondrial functional studies to a patient-derived fibroblast cell line from an individual with neuropathy that previously lacked a molecular diagnosis. RESULTS: We identified an intronic homozygous MFN2 c.600-31T>G variant that disrupts the branch point critical for intron 6 splicing. Full-length long-read isoform complementary DNA (cDNA) sequencing after treatment with a nonsense-mediated mRNA decay (NMD) inhibitor revealed that this variant creates 5 distinct altered splicing transcripts. All 5 altered splicing transcripts have disrupted open reading frames and are subject to NMD. Furthermore, a patient-derived fibroblast line demonstrated abnormal lipid droplet formation, consistent with MFN2 dysfunction. Although correctly spliced full-length MFN2 transcripts are still produced, this branch point variant results in deficient MFN2 levels and autosomal recessive Charcot-Marie-Tooth disease, axonal, type 2A (CMT2A). DISCUSSION: This case highlights the utility of full-length isoform sequencing for characterizing the molecular mechanism of undiagnosed rare diseases and expands our understanding of the genetic basis for CMT2A

Molecular pathway-based classification of ectodermal dysplasias: first five-yearly update

To keep pace with the rapid advancements in molecular genetics and rare diseases research, we have updated the list of ectodermal dysplasias based on the latest classification approach that was adopted in 2017 by an international panel of experts. For this purpose, we searched the databases PubMed and OMIM for the term “ectodermal dysplasia”, referring mainly to changes in the last 5 years. We also tried to obtain information about those diseases on which the last scientific report appeared more than 15 years ago by contacting the authors of the most recent publication. A group of experts, composed of researchers who attended the 8th International Conference on Ectodermal Dysplasias and additional members of the previous classification panel, reviewed the proposed amendments and agreed on a final table listing all 49 currently known ectodermal dysplasias for which the molecular genetic basis has been clarified, including 15 new entities. A newly reported ectodermal dysplasia, linked to the gene LRP6, is described here in more detail. These ectodermal dysplasias, in the strict sense, should be distinguished from syndromes with features of ectodermal dysplasia that are related to genes extraneous to the currently known pathways involved in ectodermal development. The latter group consists of 34 syndromes which had been placed on the previous list of ectodermal dysplasias, but most if not all of them could actually be classified elsewhere. This update should streamline the classification of ectodermal dysplasias, provide guidance to the correct diagnosis of rare disease entities, and facilitate the identification of individuals who could benefit from novel treatment options

Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome.

SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L-serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8-year-old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant-negative N-glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L-serine

Genetic Skin Disorders

This book is a readable, reliable guide to the diagnosis and differential of inherited skin disorders to which generalists, paediatricians, dermatologists, and geneticists can refer during an examination. The new edition reflects the most up-to-date understanding of the molecular and genetic bases of heritable skin diseases. Each chapter describes the signs and symptoms of heritable skin diseases and enumerates pertinent associated clinical features and differential diagnoses. Non-dermatological signs are symptoms round out the information on each condition. Where appropriate, descriptions of histopathology at both the light and electron microscopic levels are included. Over 800 full-colour photographs illustrate the concepts discussed in the text. Annotated bibliographies at the end of each section direct readers to more extensive sources, and an updated listing of support groups for patients and their families supplements the resources for medical professionals.</p

Immune Deficiency Diseases

Chediak-Higashi Disease – Chronic Granulomatous Disease – Epidermodysplasia Verruciformis – Familial Mucocutaneous Candidiasis – Griscelli Syndrome Types 1 and 2 – Job Syndrome – Mucoepithelial Dysplasia – Wiskott-Aldrich Syndrome</p

Life as We Know It: A Father, a Family, and an Exceptional Child MichaelBérubéLife as We Know It: A Father, a Family, and an Exceptional Child1996Pantheon BooksNew YorkPp. 284. $24.00

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Disorders of Pigmentation

Hyperpigmentation – Carney Complex – Dowling-Degos Disease – Dyskeratosis Congenita – Fanconi Anemia – Hemochromatosis – Incontinentia Pigmenti – LEOPARD Syndrome – Linear and Whorled Nevoid Hypermelanosis – McCune-Albright Syndrome – Naegeli Syndrome – Neurofibromatosis – Nevus Phakomatosis Pigmentovascularis – Peutz-Jeghers Syndrome – Universal Melanosis – Hypopigmentation – Albinisms – Albinism with Deafness – Hermansky-Pudlak Syndrome – Oculocutaneous Albinism Tyrosinase Negative – Oculocutaneous Albinism Tyrosinase Positive – Yellow Mutant Albinism – Cross Syndrome – Hypomelanosis of Ito – Piebaldism – Premature Canities – Vitiligo – Waardenburg Syndrome Types 1, 2, 3, and 4</p

Premature Aging

Chapter 12 covers Cockayne Syndrome, De Barsy Syndrome, Hallermann-Streiff Syndrome, Hutchinson-Gilford Progeria, and Werner Syndrome. Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.</p

Disorders of Pigmentation

Chapter 4 covers Hyperpigmentation (including Carney Complex, Dowling-Degos Disease, Dyskeratosis Congenita, Fanconi Anemia, H Syndrome, Hemochromatosis, Incontinentia Pigmenti, LEOPARD Syndrome, Linear and Whorled Nevoid Hypermelanosis, McCune-Albright Syndrome, Naegeli Syndrome, Neurofibromatosis, Nevus Phakomatosis Pigmentovascularis, Peutz-Jeghers Syndrome, and Universal Melanosis) and Hypopigmentation ( Albinisms, Albinism with Deafness, Hermansky-Pudlak Syndrome, Oculocutaneous Albinism Tyrosinase Negative, Oculocutaneous Albinism Tyrosinase Positive, Yellow Mutant Albinism, Cross Syndrome, Hypomelanosis of Ito, Piebaldism, Premature Canities, Vitiligo, and Waardenburg Syndrome Types 1, 2, 3, and 4). Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.</p