Cargando…

Reconciling newborn screening and a novel splice variant in BTD associated with partial biotinidase deficiency: a BabySeq Project case report

Here, we report a newborn female infant from the well-baby cohort of the BabySeq Project who was identified with compound heterozygous BTD gene variants. The two identified variants included a well-established pathogenic variant (c.1612C>T, p.Arg538Cys) that causes profound biotinidase deficiency...

Descripción completa

Detalles Bibliográficos
Autores principales: Murry, Jaclyn B., Machini, Kalotina, Ceyhan-Birsoy, Ozge, Kritzer, Amy, Krier, Joel B., Lebo, Matthew S., Fayer, Shawn, Genetti, Casie A., VanNoy, Grace E., Yu, Timothy W., Agrawal, Pankaj B., Parad, Richard B., Holm, Ingrid A., McGuire, Amy L., Green, Robert C., Beggs, Alan H., Rehm, Heidi L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071571/
https://www.ncbi.nlm.nih.gov/pubmed/29728376
http://dx.doi.org/10.1101/mcs.a002873
_version_ 1783343891823460352
author Murry, Jaclyn B.
Machini, Kalotina
Ceyhan-Birsoy, Ozge
Kritzer, Amy
Krier, Joel B.
Lebo, Matthew S.
Fayer, Shawn
Genetti, Casie A.
VanNoy, Grace E.
Yu, Timothy W.
Agrawal, Pankaj B.
Parad, Richard B.
Holm, Ingrid A.
McGuire, Amy L.
Green, Robert C.
Beggs, Alan H.
Rehm, Heidi L.
author_facet Murry, Jaclyn B.
Machini, Kalotina
Ceyhan-Birsoy, Ozge
Kritzer, Amy
Krier, Joel B.
Lebo, Matthew S.
Fayer, Shawn
Genetti, Casie A.
VanNoy, Grace E.
Yu, Timothy W.
Agrawal, Pankaj B.
Parad, Richard B.
Holm, Ingrid A.
McGuire, Amy L.
Green, Robert C.
Beggs, Alan H.
Rehm, Heidi L.
author_sort Murry, Jaclyn B.
collection PubMed
description Here, we report a newborn female infant from the well-baby cohort of the BabySeq Project who was identified with compound heterozygous BTD gene variants. The two identified variants included a well-established pathogenic variant (c.1612C>T, p.Arg538Cys) that causes profound biotinidase deficiency (BTD) in homozygosity. In addition, a novel splice variant (c.44+1G>A, p.?) was identified in the invariant splice donor region of intron 1, potentially predictive of loss of function. The novel variant was predicted to impact splicing of exon 1; however, given the absence of any reported pathogenic variants in exon 1 and the presence of alternative splicing with exon 1 absent in most tissues in the GTEx database, we assigned an initial classification of uncertain significance. Follow-up medical record review of state-mandated newborn screen (NBS) results revealed an initial out-of-range biotinidase activity level. Levels from a repeat NBS sample barely passed cutoff into the normal range. To determine whether the infant was biotinidase-deficient, subsequent diagnostic enzyme activity testing was performed, confirming partial BTD, and resulted in a change of management for this patient. This led to reclassification of the novel splice variant based on these results. In conclusion, combining the genetic and NBS results together prompted clinical follow-up that confirmed partial BTD and informed this novel splice site's reclassification, emphasizing the importance of combining iterative genetic and phenotypic evaluations.
format Online
Article
Text
id pubmed-6071571
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Cold Spring Harbor Laboratory Press
record_format MEDLINE/PubMed
spelling pubmed-60715712018-08-13 Reconciling newborn screening and a novel splice variant in BTD associated with partial biotinidase deficiency: a BabySeq Project case report Murry, Jaclyn B. Machini, Kalotina Ceyhan-Birsoy, Ozge Kritzer, Amy Krier, Joel B. Lebo, Matthew S. Fayer, Shawn Genetti, Casie A. VanNoy, Grace E. Yu, Timothy W. Agrawal, Pankaj B. Parad, Richard B. Holm, Ingrid A. McGuire, Amy L. Green, Robert C. Beggs, Alan H. Rehm, Heidi L. Cold Spring Harb Mol Case Stud Rapid Communication Here, we report a newborn female infant from the well-baby cohort of the BabySeq Project who was identified with compound heterozygous BTD gene variants. The two identified variants included a well-established pathogenic variant (c.1612C>T, p.Arg538Cys) that causes profound biotinidase deficiency (BTD) in homozygosity. In addition, a novel splice variant (c.44+1G>A, p.?) was identified in the invariant splice donor region of intron 1, potentially predictive of loss of function. The novel variant was predicted to impact splicing of exon 1; however, given the absence of any reported pathogenic variants in exon 1 and the presence of alternative splicing with exon 1 absent in most tissues in the GTEx database, we assigned an initial classification of uncertain significance. Follow-up medical record review of state-mandated newborn screen (NBS) results revealed an initial out-of-range biotinidase activity level. Levels from a repeat NBS sample barely passed cutoff into the normal range. To determine whether the infant was biotinidase-deficient, subsequent diagnostic enzyme activity testing was performed, confirming partial BTD, and resulted in a change of management for this patient. This led to reclassification of the novel splice variant based on these results. In conclusion, combining the genetic and NBS results together prompted clinical follow-up that confirmed partial BTD and informed this novel splice site's reclassification, emphasizing the importance of combining iterative genetic and phenotypic evaluations. Cold Spring Harbor Laboratory Press 2018-08 /pmc/articles/PMC6071571/ /pubmed/29728376 http://dx.doi.org/10.1101/mcs.a002873 Text en © 2018 Murry et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted reuse and redistribution provided that the original author and source are credited.
spellingShingle Rapid Communication
Murry, Jaclyn B.
Machini, Kalotina
Ceyhan-Birsoy, Ozge
Kritzer, Amy
Krier, Joel B.
Lebo, Matthew S.
Fayer, Shawn
Genetti, Casie A.
VanNoy, Grace E.
Yu, Timothy W.
Agrawal, Pankaj B.
Parad, Richard B.
Holm, Ingrid A.
McGuire, Amy L.
Green, Robert C.
Beggs, Alan H.
Rehm, Heidi L.
Reconciling newborn screening and a novel splice variant in BTD associated with partial biotinidase deficiency: a BabySeq Project case report
title Reconciling newborn screening and a novel splice variant in BTD associated with partial biotinidase deficiency: a BabySeq Project case report
title_full Reconciling newborn screening and a novel splice variant in BTD associated with partial biotinidase deficiency: a BabySeq Project case report
title_fullStr Reconciling newborn screening and a novel splice variant in BTD associated with partial biotinidase deficiency: a BabySeq Project case report
title_full_unstemmed Reconciling newborn screening and a novel splice variant in BTD associated with partial biotinidase deficiency: a BabySeq Project case report
title_short Reconciling newborn screening and a novel splice variant in BTD associated with partial biotinidase deficiency: a BabySeq Project case report
title_sort reconciling newborn screening and a novel splice variant in btd associated with partial biotinidase deficiency: a babyseq project case report
topic Rapid Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071571/
https://www.ncbi.nlm.nih.gov/pubmed/29728376
http://dx.doi.org/10.1101/mcs.a002873
work_keys_str_mv AT murryjaclynb reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT machinikalotina reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT ceyhanbirsoyozge reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT kritzeramy reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT krierjoelb reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT lebomatthews reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT fayershawn reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT genetticasiea reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT vannoygracee reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT yutimothyw reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT agrawalpankajb reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT paradrichardb reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT holmingrida reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT mcguireamyl reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT greenrobertc reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT beggsalanh reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT rehmheidil reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport
AT reconcilingnewbornscreeningandanovelsplicevariantinbtdassociatedwithpartialbiotinidasedeficiencyababyseqprojectcasereport