A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay

Bettina E. Mucha, Siddhart Banka, Norbert Fonya Ajeawung, Sirinart Molidperee, Gary G. Chen, Mary Kay Koenig, Rhamat B. Adejumo, Marianne Till, Michael Harbord, Renee Perrier, Emmanuelle Lemyre, Renee Myriam Boucher, Brian G. Skotko, Jessica L. Waxler, Mary Ann Thomas, Jennelle C. Hodge, Jozef Gecz, Jillian Nicholl, Lesley McGregor, Tobias Linden & 5 others Sanjay M. Sisodiya, Damien Sanlaville, Sau W. Cheung, Carl Ernst, Philippe M. Campeau

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Purpose: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes. Methods: Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed. Results: All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants. Conclusions: We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.

LanguageEnglish
Pages1058-1064
Number of pages7
JournalGenetics in Medicine
Volume21
Issue number5
DOIs
Publication statusPublished - 1 May 2019

Keywords

  • 16p13.3
  • Epilepsy
  • Microcephaly
  • Microdeletion
  • TBC1D24

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Mucha, B. E., Banka, S., Ajeawung, N. F., Molidperee, S., Chen, G. G., Koenig, M. K., ... Campeau, P. M. (2019). A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay. Genetics in Medicine, 21(5), 1058-1064. https://doi.org/10.1038/s41436-018-0290-3
Mucha, Bettina E. ; Banka, Siddhart ; Ajeawung, Norbert Fonya ; Molidperee, Sirinart ; Chen, Gary G. ; Koenig, Mary Kay ; Adejumo, Rhamat B. ; Till, Marianne ; Harbord, Michael ; Perrier, Renee ; Lemyre, Emmanuelle ; Boucher, Renee Myriam ; Skotko, Brian G. ; Waxler, Jessica L. ; Thomas, Mary Ann ; Hodge, Jennelle C. ; Gecz, Jozef ; Nicholl, Jillian ; McGregor, Lesley ; Linden, Tobias ; Sisodiya, Sanjay M. ; Sanlaville, Damien ; Cheung, Sau W. ; Ernst, Carl ; Campeau, Philippe M. / A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay. In: Genetics in Medicine. 2019 ; Vol. 21, No. 5. pp. 1058-1064.
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abstract = "Purpose: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes. Methods: Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed. Results: All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants. Conclusions: We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.",
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author = "Mucha, {Bettina E.} and Siddhart Banka and Ajeawung, {Norbert Fonya} and Sirinart Molidperee and Chen, {Gary G.} and Koenig, {Mary Kay} and Adejumo, {Rhamat B.} and Marianne Till and Michael Harbord and Renee Perrier and Emmanuelle Lemyre and Boucher, {Renee Myriam} and Skotko, {Brian G.} and Waxler, {Jessica L.} and Thomas, {Mary Ann} and Hodge, {Jennelle C.} and Jozef Gecz and Jillian Nicholl and Lesley McGregor and Tobias Linden and Sisodiya, {Sanjay M.} and Damien Sanlaville and Cheung, {Sau W.} and Carl Ernst and Campeau, {Philippe M.}",
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Mucha, BE, Banka, S, Ajeawung, NF, Molidperee, S, Chen, GG, Koenig, MK, Adejumo, RB, Till, M, Harbord, M, Perrier, R, Lemyre, E, Boucher, RM, Skotko, BG, Waxler, JL, Thomas, MA, Hodge, JC, Gecz, J, Nicholl, J, McGregor, L, Linden, T, Sisodiya, SM, Sanlaville, D, Cheung, SW, Ernst, C & Campeau, PM 2019, 'A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay', Genetics in Medicine, vol. 21, no. 5, pp. 1058-1064. https://doi.org/10.1038/s41436-018-0290-3

A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay. / Mucha, Bettina E.; Banka, Siddhart; Ajeawung, Norbert Fonya; Molidperee, Sirinart; Chen, Gary G.; Koenig, Mary Kay; Adejumo, Rhamat B.; Till, Marianne; Harbord, Michael; Perrier, Renee; Lemyre, Emmanuelle; Boucher, Renee Myriam; Skotko, Brian G.; Waxler, Jessica L.; Thomas, Mary Ann; Hodge, Jennelle C.; Gecz, Jozef; Nicholl, Jillian; McGregor, Lesley; Linden, Tobias; Sisodiya, Sanjay M.; Sanlaville, Damien; Cheung, Sau W.; Ernst, Carl; Campeau, Philippe M.

In: Genetics in Medicine, Vol. 21, No. 5, 01.05.2019, p. 1058-1064.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay

AU - Mucha, Bettina E.

AU - Banka, Siddhart

AU - Ajeawung, Norbert Fonya

AU - Molidperee, Sirinart

AU - Chen, Gary G.

AU - Koenig, Mary Kay

AU - Adejumo, Rhamat B.

AU - Till, Marianne

AU - Harbord, Michael

AU - Perrier, Renee

AU - Lemyre, Emmanuelle

AU - Boucher, Renee Myriam

AU - Skotko, Brian G.

AU - Waxler, Jessica L.

AU - Thomas, Mary Ann

AU - Hodge, Jennelle C.

AU - Gecz, Jozef

AU - Nicholl, Jillian

AU - McGregor, Lesley

AU - Linden, Tobias

AU - Sisodiya, Sanjay M.

AU - Sanlaville, Damien

AU - Cheung, Sau W.

AU - Ernst, Carl

AU - Campeau, Philippe M.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Purpose: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes. Methods: Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed. Results: All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants. Conclusions: We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.

AB - Purpose: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes. Methods: Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed. Results: All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants. Conclusions: We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.

KW - 16p13.3

KW - Epilepsy

KW - Microcephaly

KW - Microdeletion

KW - TBC1D24

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U2 - 10.1038/s41436-018-0290-3

DO - 10.1038/s41436-018-0290-3

M3 - Article

VL - 21

SP - 1058

EP - 1064

JO - Genetics in Medicine

T2 - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

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ER -