MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia

Kimberley M. Reid; Robert Spaull; Smrithi Salian; Katy Barwick; Esther Meyer; Juan Zhen; Hiromi Hirata; Diba Sheipouri; Hind Benkerroum; Kathleen M. Gorman; Apostolos Papandreou; Michael A. Simpson; Yoshinobu Hirano; Irene Farabella; Maya Topf; Detelina Grozeva; Keren Carss; Martin Smith; Hardev Pall; Peter Lunt; Susanna De Gressi; Erik‐Jan Kamsteeg; Tobias B. Haack; Lucinda Carr; Rita Guerreiro; Jose Bras; Eamonn R. Maher; Richard H. Scott; Robert J. Vandenberg; F. Lucy Raymond; Wui K. Chong; Sniya Sudhakar; Kshitij Mankad; Maarten E. Reith; Philippe M. Campeau; Robert J. Harvey; Manju A. Kurian

doi:10.1002/mds.29147

MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia

Kimberley M. Reid
, Robert Spaull
, Smrithi Salian
, Katy Barwick
, Esther Meyer
, Juan Zhen
, Hiromi Hirata
, Diba Sheipouri
, Hind Benkerroum
, Kathleen M. Gorman
, Apostolos Papandreou
, Michael A. Simpson
, Yoshinobu Hirano
, Irene Farabella
, Maya Topf
, Detelina Grozeva
, Keren Carss
, Martin Smith
, Hardev Pall
, Peter Lunt

Susanna De Gressi, Erik‐Jan Kamsteeg, Tobias B. Haack, Lucinda Carr, Rita Guerreiro, Jose Bras, Eamonn R. Maher, Richard H. Scott, Robert J. Vandenberg, F. Lucy Raymond, Wui K. Chong, Sniya Sudhakar, Kshitij Mankad, Maarten E. Reith, Philippe M. Campeau, Robert J. Harvey, Manju A. Kurian^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

12 Citations (Scopus)

365 Downloads (Pure)

Abstract

Background
Despite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders.

Objective
The objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts.

Methods
Candidate genes identified by autozygosity mapping and whole-exome sequencing were characterized using cellular and vertebrate model systems.

Results
Homozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27-related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell-surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L-proline transporter–G396S RNA. Lastly, patient fibroblasts displayed reduced cell-surface expression of glycophosphatidylinositol-anchored proteins linked to MPPE1 dysfunction.

Conclusions
We report a family harboring a homozygous MED27 variant with additional loss-of-function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Original language	English
Pages (from-to)	2139-2146
Number of pages	8
Journal	Movement Disorders
Volume	37
Issue number	10
Early online date	25 Jul 2022
DOIs	https://doi.org/10.1002/mds.29147
Publication status	Published - 17 Oct 2022

Bibliographical note

Funding Information:
This study was supported by an NIHR Professorship (M.A.K., K.M.R., R.S.), The Sir Jules Thorn Biomedical Award for Research (M.A.K., K.B.), Rosetrees Trust (M.A.K., K.M.R., K.B.), Medical Research Council (MRC) grant M013502, and National Health and Medical Research Council (NHMRC) grants APP1156673 (R.J.H.) and APP144429 (R.J.V.). E.R.M. acknowledges support and funding from the NIHR Cambridge Biomedical Research Centre. The University of Cambridge has received salary support (E.R.M.) from the National Health Service (NHS) in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. K.M.G. acknowledges funding from the Temple Street Foundation. We thank the family for their support in publishing this report. We also acknowledge William Gahl, Camilo Toro, Elizabeth Burke, and Jiayu Fu for their participation. We thank the UK10K project, largely funded by Wellcome, for their participation. We thank the Deciphering Developmental Disorders study, which presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF‐1009‐003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. We thank NIHR BioResource volunteers for their participation and gratefully acknowledge NIHR BioResource centers, NHS Trusts, and staff for their contribution. We thank the National Institute for Health Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. This study makes use of DECIPHER ( https://www.deciphergenomics.org ), which is supported by Wellcome. M.A.K., K.M.R., and R.S. were supported by an NIHR Research professorship, Sir Jules Thorn Award for Biomedical Research, and the Rosetrees Trust. We also acknowledge BioRender.com , which was used to create Figures S2 and S5 .

Funding Information:
K.M.R.: Salary supported by grant from the NIHR, with research supported by grants from NIHR and Rosetrees trust. R.S. and S. Salian: Salary supported by grants from the NIHR, Great Ormond Hospital Children's Charity, and LifeArc. K.B., E.M., J.Z., and H.H.: Salary supported by grant from the NIHR, with research supported by grants from NIHR, Sir Jules Thorne, and Rosetrees trust. D.S. and H.B.: Supported by a University of Sydney Research Training Program Scholarship. K.G.: Supported by the Temple Street Foundation. A.P., M.A.S., Y.H., I.F., and M.T.: Research supported by a joint AMR/BPNA Clinical Research Training Fellowship (GN 2465) and an NIHR (GOSH BRC) Catalyst fellowship, as well as grants from Actelion, Rosetrees Trust, and NBIA Disorders Association. D.G., K.C., M.S., H.P., P.L., S.D.G., and E.‐J.K.: Salary supported by the National Institute for Health Research and UK Research and Innovation. T.B.H., L.C., R.G., and J.B.: Supported by funding from the German Research Foundation. E.R.M., R.H.S., F.L.R., and W.K.C.: Funding from the NIHR Cambridge Biomedical Research Centre. The University of Cambridge has received salary support (E.R.M.) from the NHS in the East of England through the Clinical Academic Reserve. R.J.V., S. Sudhakar, K.M., and M.E.R.: NHMRC grant APP144429 and National Institutes of Health grant RO1 4219209. P.M.C.: Received research funding from the CIHR (Canadian Institutes of Health Research) for research unrelated to the present study. R.J.H.: MRC grant M013502 and NHMRC grant APP1156673. M.A.K.: Funding supported from NIHR Research Professorship, Sir Jules Thorn Award for Biomedical Research, and the Rosetrees Trust. The authors declare no potential conflicts of interest.

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© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Reid, K. M., Spaull, R., Salian, S., Barwick, K., Meyer, E., Zhen, J., Hirata, H., Sheipouri, D., Benkerroum, H., Gorman, K. M., Papandreou, A., Simpson, M. A., Hirano, Y., Farabella, I., Topf, M., Grozeva, D., Carss, K., Smith, M., Pall, H., ... Kurian, M. A. (2022). MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia. Movement Disorders, 37(10), 2139-2146. https://doi.org/10.1002/mds.29147

@article{e9bb499689414968805b90d5ec1640cf,

title = "MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia",

abstract = "Background Despite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders. Objective The objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts. Methods Candidate genes identified by autozygosity mapping and whole-exome sequencing were characterized using cellular and vertebrate model systems. Results Homozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27-related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell-surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L-proline transporter–G396S RNA. Lastly, patient fibroblasts displayed reduced cell-surface expression of glycophosphatidylinositol-anchored proteins linked to MPPE1 dysfunction. Conclusions We report a family harboring a homozygous MED27 variant with additional loss-of-function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. {\textcopyright} 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society",

author = "Reid, \{Kimberley M.\} and Robert Spaull and Smrithi Salian and Katy Barwick and Esther Meyer and Juan Zhen and Hiromi Hirata and Diba Sheipouri and Hind Benkerroum and Gorman, \{Kathleen M.\} and Apostolos Papandreou and Simpson, \{Michael A.\} and Yoshinobu Hirano and Irene Farabella and Maya Topf and Detelina Grozeva and Keren Carss and Martin Smith and Hardev Pall and Peter Lunt and Gressi, \{Susanna De\} and Erik‐Jan Kamsteeg and Haack, \{Tobias B.\} and Lucinda Carr and Rita Guerreiro and Jose Bras and Maher, \{Eamonn R.\} and Scott, \{Richard H.\} and Vandenberg, \{Robert J.\} and Raymond, \{F. Lucy\} and Chong, \{Wui K.\} and Sniya Sudhakar and Kshitij Mankad and Reith, \{Maarten E.\} and Campeau, \{Philippe M.\} and Harvey, \{Robert J.\} and Kurian, \{Manju A.\}",

note = "Funding Information: This study was supported by an NIHR Professorship (M.A.K., K.M.R., R.S.), The Sir Jules Thorn Biomedical Award for Research (M.A.K., K.B.), Rosetrees Trust (M.A.K., K.M.R., K.B.), Medical Research Council (MRC) grant M013502, and National Health and Medical Research Council (NHMRC) grants APP1156673 (R.J.H.) and APP144429 (R.J.V.). E.R.M. acknowledges support and funding from the NIHR Cambridge Biomedical Research Centre. The University of Cambridge has received salary support (E.R.M.) from the National Health Service (NHS) in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. K.M.G. acknowledges funding from the Temple Street Foundation. We thank the family for their support in publishing this report. We also acknowledge William Gahl, Camilo Toro, Elizabeth Burke, and Jiayu Fu for their participation. We thank the UK10K project, largely funded by Wellcome, for their participation. We thank the Deciphering Developmental Disorders study, which presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF‐1009‐003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. We thank NIHR BioResource volunteers for their participation and gratefully acknowledge NIHR BioResource centers, NHS Trusts, and staff for their contribution. We thank the National Institute for Health Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. This study makes use of DECIPHER ( https://www.deciphergenomics.org ), which is supported by Wellcome. M.A.K., K.M.R., and R.S. were supported by an NIHR Research professorship, Sir Jules Thorn Award for Biomedical Research, and the Rosetrees Trust. We also acknowledge BioRender.com , which was used to create Figures S2 and S5 . Funding Information: K.M.R.: Salary supported by grant from the NIHR, with research supported by grants from NIHR and Rosetrees trust. R.S. and S. Salian: Salary supported by grants from the NIHR, Great Ormond Hospital Children's Charity, and LifeArc. K.B., E.M., J.Z., and H.H.: Salary supported by grant from the NIHR, with research supported by grants from NIHR, Sir Jules Thorne, and Rosetrees trust. D.S. and H.B.: Supported by a University of Sydney Research Training Program Scholarship. K.G.: Supported by the Temple Street Foundation. A.P., M.A.S., Y.H., I.F., and M.T.: Research supported by a joint AMR/BPNA Clinical Research Training Fellowship (GN 2465) and an NIHR (GOSH BRC) Catalyst fellowship, as well as grants from Actelion, Rosetrees Trust, and NBIA Disorders Association. D.G., K.C., M.S., H.P., P.L., S.D.G., and E.‐J.K.: Salary supported by the National Institute for Health Research and UK Research and Innovation. T.B.H., L.C., R.G., and J.B.: Supported by funding from the German Research Foundation. E.R.M., R.H.S., F.L.R., and W.K.C.: Funding from the NIHR Cambridge Biomedical Research Centre. The University of Cambridge has received salary support (E.R.M.) from the NHS in the East of England through the Clinical Academic Reserve. R.J.V., S. Sudhakar, K.M., and M.E.R.: NHMRC grant APP144429 and National Institutes of Health grant RO1 4219209. P.M.C.: Received research funding from the CIHR (Canadian Institutes of Health Research) for research unrelated to the present study. R.J.H.: MRC grant M013502 and NHMRC grant APP1156673. M.A.K.: Funding supported from NIHR Research Professorship, Sir Jules Thorn Award for Biomedical Research, and the Rosetrees Trust. The authors declare no potential conflicts of interest. Publisher Copyright: {\textcopyright} 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.",

year = "2022",

month = oct,

day = "17",

doi = "10.1002/mds.29147",

language = "English",

volume = "37",

pages = "2139--2146",

journal = "Movement Disorders",

issn = "0885-3185",

publisher = "John Wiley \& Sons, Inc",

number = "10",

}

Reid, KM, Spaull, R, Salian, S, Barwick, K, Meyer, E, Zhen, J, Hirata, H, Sheipouri, D, Benkerroum, H, Gorman, KM, Papandreou, A, Simpson, MA, Hirano, Y, Farabella, I, Topf, M, Grozeva, D, Carss, K, Smith, M, Pall, H, Lunt, P, Gressi, SD, Kamsteeg, EJ, Haack, TB, Carr, L, Guerreiro, R, Bras, J, Maher, ER, Scott, RH, Vandenberg, RJ, Raymond, FL, Chong, WK, Sudhakar, S, Mankad, K, Reith, ME, Campeau, PM, Harvey, RJ & Kurian, MA 2022, 'MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia', Movement Disorders, vol. 37, no. 10, pp. 2139-2146. https://doi.org/10.1002/mds.29147

TY - JOUR

T1 - MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia

AU - Reid, Kimberley M.

AU - Spaull, Robert

AU - Salian, Smrithi

AU - Barwick, Katy

AU - Meyer, Esther

AU - Zhen, Juan

AU - Hirata, Hiromi

AU - Sheipouri, Diba

AU - Benkerroum, Hind

AU - Gorman, Kathleen M.

AU - Papandreou, Apostolos

AU - Simpson, Michael A.

AU - Hirano, Yoshinobu

AU - Farabella, Irene

AU - Topf, Maya

AU - Grozeva, Detelina

AU - Carss, Keren

AU - Smith, Martin

AU - Pall, Hardev

AU - Lunt, Peter

AU - Gressi, Susanna De

AU - Kamsteeg, Erik‐Jan

AU - Haack, Tobias B.

AU - Carr, Lucinda

AU - Guerreiro, Rita

AU - Bras, Jose

AU - Maher, Eamonn R.

AU - Scott, Richard H.

AU - Vandenberg, Robert J.

AU - Raymond, F. Lucy

AU - Chong, Wui K.

AU - Sudhakar, Sniya

AU - Mankad, Kshitij

AU - Reith, Maarten E.

AU - Campeau, Philippe M.

AU - Harvey, Robert J.

AU - Kurian, Manju A.

N1 - Funding Information: This study was supported by an NIHR Professorship (M.A.K., K.M.R., R.S.), The Sir Jules Thorn Biomedical Award for Research (M.A.K., K.B.), Rosetrees Trust (M.A.K., K.M.R., K.B.), Medical Research Council (MRC) grant M013502, and National Health and Medical Research Council (NHMRC) grants APP1156673 (R.J.H.) and APP144429 (R.J.V.). E.R.M. acknowledges support and funding from the NIHR Cambridge Biomedical Research Centre. The University of Cambridge has received salary support (E.R.M.) from the National Health Service (NHS) in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. K.M.G. acknowledges funding from the Temple Street Foundation. We thank the family for their support in publishing this report. We also acknowledge William Gahl, Camilo Toro, Elizabeth Burke, and Jiayu Fu for their participation. We thank the UK10K project, largely funded by Wellcome, for their participation. We thank the Deciphering Developmental Disorders study, which presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF‐1009‐003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. We thank NIHR BioResource volunteers for their participation and gratefully acknowledge NIHR BioResource centers, NHS Trusts, and staff for their contribution. We thank the National Institute for Health Research, NHS Blood and Transplant, and Health Data Research UK as part of the Digital Innovation Hub Programme. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. This study makes use of DECIPHER ( https://www.deciphergenomics.org ), which is supported by Wellcome. M.A.K., K.M.R., and R.S. were supported by an NIHR Research professorship, Sir Jules Thorn Award for Biomedical Research, and the Rosetrees Trust. We also acknowledge BioRender.com , which was used to create Figures S2 and S5 . Funding Information: K.M.R.: Salary supported by grant from the NIHR, with research supported by grants from NIHR and Rosetrees trust. R.S. and S. Salian: Salary supported by grants from the NIHR, Great Ormond Hospital Children's Charity, and LifeArc. K.B., E.M., J.Z., and H.H.: Salary supported by grant from the NIHR, with research supported by grants from NIHR, Sir Jules Thorne, and Rosetrees trust. D.S. and H.B.: Supported by a University of Sydney Research Training Program Scholarship. K.G.: Supported by the Temple Street Foundation. A.P., M.A.S., Y.H., I.F., and M.T.: Research supported by a joint AMR/BPNA Clinical Research Training Fellowship (GN 2465) and an NIHR (GOSH BRC) Catalyst fellowship, as well as grants from Actelion, Rosetrees Trust, and NBIA Disorders Association. D.G., K.C., M.S., H.P., P.L., S.D.G., and E.‐J.K.: Salary supported by the National Institute for Health Research and UK Research and Innovation. T.B.H., L.C., R.G., and J.B.: Supported by funding from the German Research Foundation. E.R.M., R.H.S., F.L.R., and W.K.C.: Funding from the NIHR Cambridge Biomedical Research Centre. The University of Cambridge has received salary support (E.R.M.) from the NHS in the East of England through the Clinical Academic Reserve. R.J.V., S. Sudhakar, K.M., and M.E.R.: NHMRC grant APP144429 and National Institutes of Health grant RO1 4219209. P.M.C.: Received research funding from the CIHR (Canadian Institutes of Health Research) for research unrelated to the present study. R.J.H.: MRC grant M013502 and NHMRC grant APP1156673. M.A.K.: Funding supported from NIHR Research Professorship, Sir Jules Thorn Award for Biomedical Research, and the Rosetrees Trust. The authors declare no potential conflicts of interest. Publisher Copyright: © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

PY - 2022/10/17

Y1 - 2022/10/17

N2 - Background Despite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders. Objective The objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts. Methods Candidate genes identified by autozygosity mapping and whole-exome sequencing were characterized using cellular and vertebrate model systems. Results Homozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27-related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell-surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L-proline transporter–G396S RNA. Lastly, patient fibroblasts displayed reduced cell-surface expression of glycophosphatidylinositol-anchored proteins linked to MPPE1 dysfunction. Conclusions We report a family harboring a homozygous MED27 variant with additional loss-of-function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

AB - Background Despite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders. Objective The objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts. Methods Candidate genes identified by autozygosity mapping and whole-exome sequencing were characterized using cellular and vertebrate model systems. Results Homozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27-related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell-surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L-proline transporter–G396S RNA. Lastly, patient fibroblasts displayed reduced cell-surface expression of glycophosphatidylinositol-anchored proteins linked to MPPE1 dysfunction. Conclusions We report a family harboring a homozygous MED27 variant with additional loss-of-function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

UR - https://doi.org/10.1002/mds.29147

U2 - 10.1002/mds.29147

DO - 10.1002/mds.29147

M3 - Article (Academic Journal)

C2 - 35876425

SN - 0885-3185

VL - 37

SP - 2139

EP - 2146

JO - Movement Disorders

JF - Movement Disorders

IS - 10

ER -

MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia

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