De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay

Jessica X. Chong, Margaret J. McMillin, Kathryn M. Shively, Anita E. Beck, Colby T. Marvin, Jose R. Armenteros, Kati J. Buckingham, Naomi T. Nkinsi, Evan A. Boyle, Margaret N. Berry, Maureen Bocian, Nicola Foulds, Maria Luisa Giovannucci Uzielli, Chad Haldeman-Englert, Raoul C M Hennekam, Paige Kaplan, Antonie D. Kline, Catherine L. Mercer, Malgorzata J M Nowaczyk, Jolien S. Klein Wassink-Ruiter & 13 others Elizabeth W. McPherson, Regina A. Moreno, Angela E. Scheuerle, Vandana Shashi, Cathy A. Stevens, John C. Carey, Arnaud Monteil, Philippe Lory, Holly K. Tabor, Joshua D. Smith, Jay Shendure, Deborah A. Nickerson, Michael J. Bamshad

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Abstract

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).

Original languageEnglish (US)
Pages (from-to)462-473
Number of pages12
JournalAmerican Journal of Human Genetics
Volume96
Issue number3
DOIs
StatePublished - Mar 5 2015

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Muscle Hypotonia
Contracture
Arthrogryposis
Extremities
Mutation
Exome
Missense Mutation
S 6
Molecular Probes
Sodium Channels
Intellectual Disability
Amino Acids
Freeman-Sheldon syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. / Chong, Jessica X.; McMillin, Margaret J.; Shively, Kathryn M.; Beck, Anita E.; Marvin, Colby T.; Armenteros, Jose R.; Buckingham, Kati J.; Nkinsi, Naomi T.; Boyle, Evan A.; Berry, Margaret N.; Bocian, Maureen; Foulds, Nicola; Uzielli, Maria Luisa Giovannucci; Haldeman-Englert, Chad; Hennekam, Raoul C M; Kaplan, Paige; Kline, Antonie D.; Mercer, Catherine L.; Nowaczyk, Malgorzata J M; Klein Wassink-Ruiter, Jolien S.; McPherson, Elizabeth W.; Moreno, Regina A.; Scheuerle, Angela E.; Shashi, Vandana; Stevens, Cathy A.; Carey, John C.; Monteil, Arnaud; Lory, Philippe; Tabor, Holly K.; Smith, Joshua D.; Shendure, Jay; Nickerson, Deborah A.; Bamshad, Michael J.

In: American Journal of Human Genetics, Vol. 96, No. 3, 05.03.2015, p. 462-473.

Research output: Contribution to journalArticle

Chong, JX, McMillin, MJ, Shively, KM, Beck, AE, Marvin, CT, Armenteros, JR, Buckingham, KJ, Nkinsi, NT, Boyle, EA, Berry, MN, Bocian, M, Foulds, N, Uzielli, MLG, Haldeman-Englert, C, Hennekam, RCM, Kaplan, P, Kline, AD, Mercer, CL, Nowaczyk, MJM, Klein Wassink-Ruiter, JS, McPherson, EW, Moreno, RA, Scheuerle, AE, Shashi, V, Stevens, CA, Carey, JC, Monteil, A, Lory, P, Tabor, HK, Smith, JD, Shendure, J, Nickerson, DA & Bamshad, MJ 2015, 'De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay', American Journal of Human Genetics, vol. 96, no. 3, pp. 462-473. https://doi.org/10.1016/j.ajhg.2015.01.003
Chong, Jessica X. ; McMillin, Margaret J. ; Shively, Kathryn M. ; Beck, Anita E. ; Marvin, Colby T. ; Armenteros, Jose R. ; Buckingham, Kati J. ; Nkinsi, Naomi T. ; Boyle, Evan A. ; Berry, Margaret N. ; Bocian, Maureen ; Foulds, Nicola ; Uzielli, Maria Luisa Giovannucci ; Haldeman-Englert, Chad ; Hennekam, Raoul C M ; Kaplan, Paige ; Kline, Antonie D. ; Mercer, Catherine L. ; Nowaczyk, Malgorzata J M ; Klein Wassink-Ruiter, Jolien S. ; McPherson, Elizabeth W. ; Moreno, Regina A. ; Scheuerle, Angela E. ; Shashi, Vandana ; Stevens, Cathy A. ; Carey, John C. ; Monteil, Arnaud ; Lory, Philippe ; Tabor, Holly K. ; Smith, Joshua D. ; Shendure, Jay ; Nickerson, Deborah A. ; Bamshad, Michael J. / De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay. In: American Journal of Human Genetics. 2015 ; Vol. 96, No. 3. pp. 462-473.
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title = "De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay",
abstract = "Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with {"}DA2A with severe neurological abnormalities{"} and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with {"}atypical{"} forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).",
author = "Chong, {Jessica X.} and McMillin, {Margaret J.} and Shively, {Kathryn M.} and Beck, {Anita E.} and Marvin, {Colby T.} and Armenteros, {Jose R.} and Buckingham, {Kati J.} and Nkinsi, {Naomi T.} and Boyle, {Evan A.} and Berry, {Margaret N.} and Maureen Bocian and Nicola Foulds and Uzielli, {Maria Luisa Giovannucci} and Chad Haldeman-Englert and Hennekam, {Raoul C M} and Paige Kaplan and Kline, {Antonie D.} and Mercer, {Catherine L.} and Nowaczyk, {Malgorzata J M} and {Klein Wassink-Ruiter}, {Jolien S.} and McPherson, {Elizabeth W.} and Moreno, {Regina A.} and Scheuerle, {Angela E.} and Vandana Shashi and Stevens, {Cathy A.} and Carey, {John C.} and Arnaud Monteil and Philippe Lory and Tabor, {Holly K.} and Smith, {Joshua D.} and Jay Shendure and Nickerson, {Deborah A.} and Bamshad, {Michael J.}",
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T1 - De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay

AU - Chong, Jessica X.

AU - McMillin, Margaret J.

AU - Shively, Kathryn M.

AU - Beck, Anita E.

AU - Marvin, Colby T.

AU - Armenteros, Jose R.

AU - Buckingham, Kati J.

AU - Nkinsi, Naomi T.

AU - Boyle, Evan A.

AU - Berry, Margaret N.

AU - Bocian, Maureen

AU - Foulds, Nicola

AU - Uzielli, Maria Luisa Giovannucci

AU - Haldeman-Englert, Chad

AU - Hennekam, Raoul C M

AU - Kaplan, Paige

AU - Kline, Antonie D.

AU - Mercer, Catherine L.

AU - Nowaczyk, Malgorzata J M

AU - Klein Wassink-Ruiter, Jolien S.

AU - McPherson, Elizabeth W.

AU - Moreno, Regina A.

AU - Scheuerle, Angela E.

AU - Shashi, Vandana

AU - Stevens, Cathy A.

AU - Carey, John C.

AU - Monteil, Arnaud

AU - Lory, Philippe

AU - Tabor, Holly K.

AU - Smith, Joshua D.

AU - Shendure, Jay

AU - Nickerson, Deborah A.

AU - Bamshad, Michael J.

PY - 2015/3/5

Y1 - 2015/3/5

N2 - Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).

AB - Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).

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