Implication of LRRC4C and DPP6 in neurodevelopmental disorders

Gilles Maussion, Cristiana Cruceanu, Jill A. Rosenfeld, Scott C. Bell, Fabrice Jollant, Jin Szatkiewicz, Ryan L. Collins, Carrie Hanscom, Ilaria Kolobova, Nicolas Menjot de Champfleur, Ian Blumenthal, Colby Chiang, Vanessa Ota, Christina Hultman, Colm O'Dushlaine, Steve McCarroll, Martin Alda, Sebastien Jacquemont, Zehra Ordulu, Christian R. MarshallMelissa T. Carter, Lisa G. Shaffer, Pamela Sklar, Santhosh Girirajan, Cynthia C. Morton, James F. Gusella, Gustavo Turecki, Dimitri J. Stavropoulos, Patrick F. Sullivan, Stephen W. Scherer, Michael E. Talkowski, Carl Ernst

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11.2, 1q44, and 2q33.1 CN syndromes, suggesting LRRC4C deletion variants may be modifiers of neurodevelopmental disorders. In vitro, functional assessments modeling patient deletions in LRRC4C suggest a negative regulatory role of these exons found in the untranslated region of LRRC4C, which has a single, terminal coding exon. These data suggest that the proband's autism may be due to the inheritance of disruptions in both DPP6 and LRRC4C, and may highlight the importance of the netrin G family and potassium channel interacting molecules in neurodevelopmental disorders.

Original languageEnglish (US)
Pages (from-to)395-406
Number of pages12
JournalAmerican Journal of Medical Genetics, Part A
Volume173
Issue number2
DOIs
StatePublished - Feb 1 2017

Fingerprint

Autistic Disorder
Kv Channel-Interacting Proteins
Exons
Sensation Disorders
Untranslated Regions
Phenotype
Apraxias
Potassium Channels
Psychiatry
Genome
Neurodevelopmental Disorders
In Vitro Techniques
Paternal Inheritance
Maternal Inheritance
Axon Guidance

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Maussion, G., Cruceanu, C., Rosenfeld, J. A., Bell, S. C., Jollant, F., Szatkiewicz, J., ... Ernst, C. (2017). Implication of LRRC4C and DPP6 in neurodevelopmental disorders. American Journal of Medical Genetics, Part A, 173(2), 395-406. https://doi.org/10.1002/ajmg.a.38021
Maussion, Gilles ; Cruceanu, Cristiana ; Rosenfeld, Jill A. ; Bell, Scott C. ; Jollant, Fabrice ; Szatkiewicz, Jin ; Collins, Ryan L. ; Hanscom, Carrie ; Kolobova, Ilaria ; de Champfleur, Nicolas Menjot ; Blumenthal, Ian ; Chiang, Colby ; Ota, Vanessa ; Hultman, Christina ; O'Dushlaine, Colm ; McCarroll, Steve ; Alda, Martin ; Jacquemont, Sebastien ; Ordulu, Zehra ; Marshall, Christian R. ; Carter, Melissa T. ; Shaffer, Lisa G. ; Sklar, Pamela ; Girirajan, Santhosh ; Morton, Cynthia C. ; Gusella, James F. ; Turecki, Gustavo ; Stavropoulos, Dimitri J. ; Sullivan, Patrick F. ; Scherer, Stephen W. ; Talkowski, Michael E. ; Ernst, Carl. / Implication of LRRC4C and DPP6 in neurodevelopmental disorders. In: American Journal of Medical Genetics, Part A. 2017 ; Vol. 173, No. 2. pp. 395-406.
@article{f916b87ea2f547a98ea4a167eaf57f48,
title = "Implication of LRRC4C and DPP6 in neurodevelopmental disorders",
abstract = "We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60{\%} of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11.2, 1q44, and 2q33.1 CN syndromes, suggesting LRRC4C deletion variants may be modifiers of neurodevelopmental disorders. In vitro, functional assessments modeling patient deletions in LRRC4C suggest a negative regulatory role of these exons found in the untranslated region of LRRC4C, which has a single, terminal coding exon. These data suggest that the proband's autism may be due to the inheritance of disruptions in both DPP6 and LRRC4C, and may highlight the importance of the netrin G family and potassium channel interacting molecules in neurodevelopmental disorders.",
author = "Gilles Maussion and Cristiana Cruceanu and Rosenfeld, {Jill A.} and Bell, {Scott C.} and Fabrice Jollant and Jin Szatkiewicz and Collins, {Ryan L.} and Carrie Hanscom and Ilaria Kolobova and {de Champfleur}, {Nicolas Menjot} and Ian Blumenthal and Colby Chiang and Vanessa Ota and Christina Hultman and Colm O'Dushlaine and Steve McCarroll and Martin Alda and Sebastien Jacquemont and Zehra Ordulu and Marshall, {Christian R.} and Carter, {Melissa T.} and Shaffer, {Lisa G.} and Pamela Sklar and Santhosh Girirajan and Morton, {Cynthia C.} and Gusella, {James F.} and Gustavo Turecki and Stavropoulos, {Dimitri J.} and Sullivan, {Patrick F.} and Scherer, {Stephen W.} and Talkowski, {Michael E.} and Carl Ernst",
year = "2017",
month = "2",
day = "1",
doi = "10.1002/ajmg.a.38021",
language = "English (US)",
volume = "173",
pages = "395--406",
journal = "American Journal of Medical Genetics, Part A",
issn = "1552-4825",
publisher = "Wiley-Liss Inc.",
number = "2",

}

Maussion, G, Cruceanu, C, Rosenfeld, JA, Bell, SC, Jollant, F, Szatkiewicz, J, Collins, RL, Hanscom, C, Kolobova, I, de Champfleur, NM, Blumenthal, I, Chiang, C, Ota, V, Hultman, C, O'Dushlaine, C, McCarroll, S, Alda, M, Jacquemont, S, Ordulu, Z, Marshall, CR, Carter, MT, Shaffer, LG, Sklar, P, Girirajan, S, Morton, CC, Gusella, JF, Turecki, G, Stavropoulos, DJ, Sullivan, PF, Scherer, SW, Talkowski, ME & Ernst, C 2017, 'Implication of LRRC4C and DPP6 in neurodevelopmental disorders', American Journal of Medical Genetics, Part A, vol. 173, no. 2, pp. 395-406. https://doi.org/10.1002/ajmg.a.38021

Implication of LRRC4C and DPP6 in neurodevelopmental disorders. / Maussion, Gilles; Cruceanu, Cristiana; Rosenfeld, Jill A.; Bell, Scott C.; Jollant, Fabrice; Szatkiewicz, Jin; Collins, Ryan L.; Hanscom, Carrie; Kolobova, Ilaria; de Champfleur, Nicolas Menjot; Blumenthal, Ian; Chiang, Colby; Ota, Vanessa; Hultman, Christina; O'Dushlaine, Colm; McCarroll, Steve; Alda, Martin; Jacquemont, Sebastien; Ordulu, Zehra; Marshall, Christian R.; Carter, Melissa T.; Shaffer, Lisa G.; Sklar, Pamela; Girirajan, Santhosh; Morton, Cynthia C.; Gusella, James F.; Turecki, Gustavo; Stavropoulos, Dimitri J.; Sullivan, Patrick F.; Scherer, Stephen W.; Talkowski, Michael E.; Ernst, Carl.

In: American Journal of Medical Genetics, Part A, Vol. 173, No. 2, 01.02.2017, p. 395-406.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Implication of LRRC4C and DPP6 in neurodevelopmental disorders

AU - Maussion, Gilles

AU - Cruceanu, Cristiana

AU - Rosenfeld, Jill A.

AU - Bell, Scott C.

AU - Jollant, Fabrice

AU - Szatkiewicz, Jin

AU - Collins, Ryan L.

AU - Hanscom, Carrie

AU - Kolobova, Ilaria

AU - de Champfleur, Nicolas Menjot

AU - Blumenthal, Ian

AU - Chiang, Colby

AU - Ota, Vanessa

AU - Hultman, Christina

AU - O'Dushlaine, Colm

AU - McCarroll, Steve

AU - Alda, Martin

AU - Jacquemont, Sebastien

AU - Ordulu, Zehra

AU - Marshall, Christian R.

AU - Carter, Melissa T.

AU - Shaffer, Lisa G.

AU - Sklar, Pamela

AU - Girirajan, Santhosh

AU - Morton, Cynthia C.

AU - Gusella, James F.

AU - Turecki, Gustavo

AU - Stavropoulos, Dimitri J.

AU - Sullivan, Patrick F.

AU - Scherer, Stephen W.

AU - Talkowski, Michael E.

AU - Ernst, Carl

PY - 2017/2/1

Y1 - 2017/2/1

N2 - We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11.2, 1q44, and 2q33.1 CN syndromes, suggesting LRRC4C deletion variants may be modifiers of neurodevelopmental disorders. In vitro, functional assessments modeling patient deletions in LRRC4C suggest a negative regulatory role of these exons found in the untranslated region of LRRC4C, which has a single, terminal coding exon. These data suggest that the proband's autism may be due to the inheritance of disruptions in both DPP6 and LRRC4C, and may highlight the importance of the netrin G family and potassium channel interacting molecules in neurodevelopmental disorders.

AB - We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11.2, 1q44, and 2q33.1 CN syndromes, suggesting LRRC4C deletion variants may be modifiers of neurodevelopmental disorders. In vitro, functional assessments modeling patient deletions in LRRC4C suggest a negative regulatory role of these exons found in the untranslated region of LRRC4C, which has a single, terminal coding exon. These data suggest that the proband's autism may be due to the inheritance of disruptions in both DPP6 and LRRC4C, and may highlight the importance of the netrin G family and potassium channel interacting molecules in neurodevelopmental disorders.

UR - http://www.scopus.com/inward/record.url?scp=84995484522&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84995484522&partnerID=8YFLogxK

U2 - 10.1002/ajmg.a.38021

DO - 10.1002/ajmg.a.38021

M3 - Article

C2 - 27759917

AN - SCOPUS:84995484522

VL - 173

SP - 395

EP - 406

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

SN - 1552-4825

IS - 2

ER -

Maussion G, Cruceanu C, Rosenfeld JA, Bell SC, Jollant F, Szatkiewicz J et al. Implication of LRRC4C and DPP6 in neurodevelopmental disorders. American Journal of Medical Genetics, Part A. 2017 Feb 1;173(2):395-406. https://doi.org/10.1002/ajmg.a.38021