Cargando…

Compound heterozygous SLC19A3 mutations further refine the critical promoter region for biotin-thiamine-responsive basal ganglia disease

Mutations in the gene SLC19A3 result in thiamine metabolism dysfunction syndrome 2, also known as biotin-thiamine-responsive basal ganglia disease (BTBGD). This neurometabolic disease typically presents in early childhood with progressive neurodegeneration, including confusion, seizures, and dysphag...

Descripción completa

Detalles Bibliográficos
Autores principales: Whitford, Whitney, Hawkins, Isobel, Glamuzina, Emma, Wilson, Francessa, Marshall, Andrew, Ashton, Fern, Love, Donald R., Taylor, Juliet, Hill, Rosamund, Lehnert, Klaus, Snell, Russell G., Jacobsen, Jessie C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701311/
https://www.ncbi.nlm.nih.gov/pubmed/28696212
http://dx.doi.org/10.1101/mcs.a001909
_version_ 1783281313364574208
author Whitford, Whitney
Hawkins, Isobel
Glamuzina, Emma
Wilson, Francessa
Marshall, Andrew
Ashton, Fern
Love, Donald R.
Taylor, Juliet
Hill, Rosamund
Lehnert, Klaus
Snell, Russell G.
Jacobsen, Jessie C.
author_facet Whitford, Whitney
Hawkins, Isobel
Glamuzina, Emma
Wilson, Francessa
Marshall, Andrew
Ashton, Fern
Love, Donald R.
Taylor, Juliet
Hill, Rosamund
Lehnert, Klaus
Snell, Russell G.
Jacobsen, Jessie C.
author_sort Whitford, Whitney
collection PubMed
description Mutations in the gene SLC19A3 result in thiamine metabolism dysfunction syndrome 2, also known as biotin-thiamine-responsive basal ganglia disease (BTBGD). This neurometabolic disease typically presents in early childhood with progressive neurodegeneration, including confusion, seizures, and dysphagia, advancing to coma and death. Treatment is possible via supplement of biotin and/or thiamine, with early treatment resulting in significant lifelong improvements. Here we report two siblings who received a refined diagnosis of BTBGD following whole-genome sequencing. Both children inherited compound heterozygous mutations from unaffected parents; a missense single-nucleotide variant (p.G23V) in the first transmembrane domain of the protein, and a 4808-bp deletion in exon 1 encompassing the 5′ UTR and minimal promoter region. This deletion is the smallest promoter deletion reported to date, further defining the minimal promoter region of SLC19A3. Unfortunately, one of the siblings died prior to diagnosis, but the other is showing significant improvement after commencement of therapy. This case demonstrates the power of whole-genome sequencing for the identification of structural variants and subsequent diagnosis of rare neurodevelopmental disorders.
format Online
Article
Text
id pubmed-5701311
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Cold Spring Harbor Laboratory Press
record_format MEDLINE/PubMed
spelling pubmed-57013112017-12-04 Compound heterozygous SLC19A3 mutations further refine the critical promoter region for biotin-thiamine-responsive basal ganglia disease Whitford, Whitney Hawkins, Isobel Glamuzina, Emma Wilson, Francessa Marshall, Andrew Ashton, Fern Love, Donald R. Taylor, Juliet Hill, Rosamund Lehnert, Klaus Snell, Russell G. Jacobsen, Jessie C. Cold Spring Harb Mol Case Stud Research Report Mutations in the gene SLC19A3 result in thiamine metabolism dysfunction syndrome 2, also known as biotin-thiamine-responsive basal ganglia disease (BTBGD). This neurometabolic disease typically presents in early childhood with progressive neurodegeneration, including confusion, seizures, and dysphagia, advancing to coma and death. Treatment is possible via supplement of biotin and/or thiamine, with early treatment resulting in significant lifelong improvements. Here we report two siblings who received a refined diagnosis of BTBGD following whole-genome sequencing. Both children inherited compound heterozygous mutations from unaffected parents; a missense single-nucleotide variant (p.G23V) in the first transmembrane domain of the protein, and a 4808-bp deletion in exon 1 encompassing the 5′ UTR and minimal promoter region. This deletion is the smallest promoter deletion reported to date, further defining the minimal promoter region of SLC19A3. Unfortunately, one of the siblings died prior to diagnosis, but the other is showing significant improvement after commencement of therapy. This case demonstrates the power of whole-genome sequencing for the identification of structural variants and subsequent diagnosis of rare neurodevelopmental disorders. Cold Spring Harbor Laboratory Press 2017-11 /pmc/articles/PMC5701311/ /pubmed/28696212 http://dx.doi.org/10.1101/mcs.a001909 Text en © 2017 Whitford et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Research Report
Whitford, Whitney
Hawkins, Isobel
Glamuzina, Emma
Wilson, Francessa
Marshall, Andrew
Ashton, Fern
Love, Donald R.
Taylor, Juliet
Hill, Rosamund
Lehnert, Klaus
Snell, Russell G.
Jacobsen, Jessie C.
Compound heterozygous SLC19A3 mutations further refine the critical promoter region for biotin-thiamine-responsive basal ganglia disease
title Compound heterozygous SLC19A3 mutations further refine the critical promoter region for biotin-thiamine-responsive basal ganglia disease
title_full Compound heterozygous SLC19A3 mutations further refine the critical promoter region for biotin-thiamine-responsive basal ganglia disease
title_fullStr Compound heterozygous SLC19A3 mutations further refine the critical promoter region for biotin-thiamine-responsive basal ganglia disease
title_full_unstemmed Compound heterozygous SLC19A3 mutations further refine the critical promoter region for biotin-thiamine-responsive basal ganglia disease
title_short Compound heterozygous SLC19A3 mutations further refine the critical promoter region for biotin-thiamine-responsive basal ganglia disease
title_sort compound heterozygous slc19a3 mutations further refine the critical promoter region for biotin-thiamine-responsive basal ganglia disease
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701311/
https://www.ncbi.nlm.nih.gov/pubmed/28696212
http://dx.doi.org/10.1101/mcs.a001909
work_keys_str_mv AT whitfordwhitney compoundheterozygousslc19a3mutationsfurtherrefinethecriticalpromoterregionforbiotinthiamineresponsivebasalgangliadisease
AT hawkinsisobel compoundheterozygousslc19a3mutationsfurtherrefinethecriticalpromoterregionforbiotinthiamineresponsivebasalgangliadisease
AT glamuzinaemma compoundheterozygousslc19a3mutationsfurtherrefinethecriticalpromoterregionforbiotinthiamineresponsivebasalgangliadisease
AT wilsonfrancessa compoundheterozygousslc19a3mutationsfurtherrefinethecriticalpromoterregionforbiotinthiamineresponsivebasalgangliadisease
AT marshallandrew compoundheterozygousslc19a3mutationsfurtherrefinethecriticalpromoterregionforbiotinthiamineresponsivebasalgangliadisease
AT ashtonfern compoundheterozygousslc19a3mutationsfurtherrefinethecriticalpromoterregionforbiotinthiamineresponsivebasalgangliadisease
AT lovedonaldr compoundheterozygousslc19a3mutationsfurtherrefinethecriticalpromoterregionforbiotinthiamineresponsivebasalgangliadisease
AT taylorjuliet compoundheterozygousslc19a3mutationsfurtherrefinethecriticalpromoterregionforbiotinthiamineresponsivebasalgangliadisease
AT hillrosamund compoundheterozygousslc19a3mutationsfurtherrefinethecriticalpromoterregionforbiotinthiamineresponsivebasalgangliadisease
AT lehnertklaus compoundheterozygousslc19a3mutationsfurtherrefinethecriticalpromoterregionforbiotinthiamineresponsivebasalgangliadisease
AT snellrussellg compoundheterozygousslc19a3mutationsfurtherrefinethecriticalpromoterregionforbiotinthiamineresponsivebasalgangliadisease
AT jacobsenjessiec compoundheterozygousslc19a3mutationsfurtherrefinethecriticalpromoterregionforbiotinthiamineresponsivebasalgangliadisease