A de novo CTNNB1 nonsense mutation associated with syndromic atypical hyperekplexia, microcephaly and intellectual disability: a case report

doi:10.1186/s12883-016-0554-y

Case Reports

. 2016 Mar 12:16:35.

doi: 10.1186/s12883-016-0554-y.

A de novo CTNNB1 nonsense mutation associated with syndromic atypical hyperekplexia, microcephaly and intellectual disability: a case report

Anna Winczewska-Wiktor¹, Magdalena Badura-Stronka², Anna Monies-Nowicka³, Michal Maciej Nowicki³, Barbara Steinborn¹, Anna Latos-Bieleńska⁴, Dorota Monies⁵

Affiliations

¹ Chair and Department of Child Neurology, Poznan University of Medical Sciences, Poznan, Poland.
² Chair and Department of Medical Genetics, Poznan University of Medical Sciences, ul. Rokietnicka 8, 60-608, Poznań, Poland. bstronka@gmail.com.
³ Poznan University of Medical Sciences, Poznan, Poland.
⁴ Chair and Department of Medical Genetics, Poznan University of Medical Sciences, ul. Rokietnicka 8, 60-608, Poznań, Poland.
⁵ Department of Genetics, King Faisal Hospital and Research Centre, Riyadh, Saudi Arabia.

PMID: 26968164
PMCID: PMC4788907
DOI: 10.1186/s12883-016-0554-y

Case Reports

A de novo CTNNB1 nonsense mutation associated with syndromic atypical hyperekplexia, microcephaly and intellectual disability: a case report

Anna Winczewska-Wiktor et al. BMC Neurol. 2016.

. 2016 Mar 12:16:35.

doi: 10.1186/s12883-016-0554-y.

Authors

Anna Winczewska-Wiktor¹, Magdalena Badura-Stronka², Anna Monies-Nowicka³, Michal Maciej Nowicki³, Barbara Steinborn¹, Anna Latos-Bieleńska⁴, Dorota Monies⁵

Affiliations

¹ Chair and Department of Child Neurology, Poznan University of Medical Sciences, Poznan, Poland.
² Chair and Department of Medical Genetics, Poznan University of Medical Sciences, ul. Rokietnicka 8, 60-608, Poznań, Poland. bstronka@gmail.com.
³ Poznan University of Medical Sciences, Poznan, Poland.
⁴ Chair and Department of Medical Genetics, Poznan University of Medical Sciences, ul. Rokietnicka 8, 60-608, Poznań, Poland.
⁵ Department of Genetics, King Faisal Hospital and Research Centre, Riyadh, Saudi Arabia.

PMID: 26968164
PMCID: PMC4788907
DOI: 10.1186/s12883-016-0554-y

Abstract

Background: In addition to its role in cell adhesion and gene expression in the canonical Wingless/integrated Wnt signaling pathway, β-catenin also regulates genes that underlie the transmission of nerve impulses. Mutations of CTNNB1 (β-catenin) have recently been described in patients with a wide range of neurodevelopmental disorders (intellectual disability, microcephaly and other syndromic features). We for the first time associate CTNNB1 mutation with hyperekplexia identifying it as an additional candidate for consideration in patients with startle syndrome.

Case presentation: We describe an 11 year old male Polish patient with a de novo nonsense mutation in CTNNB1 who in addition to the major features of CTNNB1-related syndrome including intellectual disability and microcephaly, exhibited hyperekplexia and apraxia of upward gaze. The patient became symptomatic at the age of 20 months exhibiting delayed speech and psychomotor development. Social and emotional development was normal but mild hyperactivity was noted. Episodic falls when startled by noise or touch were observed from the age of 8.5 years, progressively increasing but never with loss of consciousness. Targeted gene panel next generation sequencing (NGS) and patient-parents trio analysis revealed a heterozygous de novo nonsense mutation in exon 3 of CTNNB1 identifying a novel association of β-catenin with hyperekplexia.

Conclusion: We report for the first time a clear association of mutation in CTNNB1 with an atypical syndromic heperekplexia expanding the phenotype of CTNNB1-related syndrome. Consequently CTNNB1 should be added to the growing list of genes to be considered as a cause of startle disease or syndromic hyperekplexia.

Keywords: Hyperekplexia; Intellectual disability; Microcephaly; β-catenin.

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Figures

**Fig. 1**
Filtering strategy used for identification of a causative mutation using trio analysis and NGS-gene panel (a). DNA electrophoregram with the c.C232T; p.Q78X mutation in exon 3 of *CTNNB1* (b)

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References

1. de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367(20):1921–1929. doi: 10.1056/NEJMoa1206524. - DOI - PubMed
1. Kuechler A, Willemsen MH, Albrecht B, Bacino CA, Bartholomew DW, van Bokhoven H, et al. De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum. Hum Genet. 2015;134(1):97–109. doi: 10.1007/s00439-014-1498-1. - DOI - PubMed
1. Tucci V, Kleefstra T, Hardy A, Heise I, Maggi S, Willemsen MH, et al. Dominant beta-catenin mutations cause intellectual disability with recognizable syndromic features. J Clin Invest. 2014;124(4):1468–1482. doi: 10.1172/JCI70372. - DOI - PMC - PubMed
1. Dubruc E, Putoux A, Labalme A, Rougeot C, Sanlaville D, Edery P. A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency. Am J Med Genet A. 2014;164A(6):1571–1575. doi: 10.1002/ajmg.a.36484. - DOI - PubMed
1. Al-Futaisi AM, Al-Kindi MN, Al-Mawali AM, Koul RL, Al-Adawi S, Al-Yahyaee SA. Novel mutation of GLRA1 in Omani families with hyperekplexia and mild mental retardation. Pediatr Neurol. 2012;46(2):89–93. doi: 10.1016/j.pediatrneurol.2011.11.008. - DOI - PubMed

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[1] de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367(20):1921–1929. doi: 10.1056/NEJMoa1206524. - DOI - PubMed

[2] de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367(20):1921–1929. doi: 10.1056/NEJMoa1206524. - DOI - PubMed

[3] Kuechler A, Willemsen MH, Albrecht B, Bacino CA, Bartholomew DW, van Bokhoven H, et al. De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum. Hum Genet. 2015;134(1):97–109. doi: 10.1007/s00439-014-1498-1. - DOI - PubMed

[4] Kuechler A, Willemsen MH, Albrecht B, Bacino CA, Bartholomew DW, van Bokhoven H, et al. De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum. Hum Genet. 2015;134(1):97–109. doi: 10.1007/s00439-014-1498-1. - DOI - PubMed

[5] Tucci V, Kleefstra T, Hardy A, Heise I, Maggi S, Willemsen MH, et al. Dominant beta-catenin mutations cause intellectual disability with recognizable syndromic features. J Clin Invest. 2014;124(4):1468–1482. doi: 10.1172/JCI70372. - DOI - PMC - PubMed

[6] Tucci V, Kleefstra T, Hardy A, Heise I, Maggi S, Willemsen MH, et al. Dominant beta-catenin mutations cause intellectual disability with recognizable syndromic features. J Clin Invest. 2014;124(4):1468–1482. doi: 10.1172/JCI70372. - DOI - PMC - PubMed

[7] Dubruc E, Putoux A, Labalme A, Rougeot C, Sanlaville D, Edery P. A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency. Am J Med Genet A. 2014;164A(6):1571–1575. doi: 10.1002/ajmg.a.36484. - DOI - PubMed

[8] Dubruc E, Putoux A, Labalme A, Rougeot C, Sanlaville D, Edery P. A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency. Am J Med Genet A. 2014;164A(6):1571–1575. doi: 10.1002/ajmg.a.36484. - DOI - PubMed

[9] Al-Futaisi AM, Al-Kindi MN, Al-Mawali AM, Koul RL, Al-Adawi S, Al-Yahyaee SA. Novel mutation of GLRA1 in Omani families with hyperekplexia and mild mental retardation. Pediatr Neurol. 2012;46(2):89–93. doi: 10.1016/j.pediatrneurol.2011.11.008. - DOI - PubMed

[10] Al-Futaisi AM, Al-Kindi MN, Al-Mawali AM, Koul RL, Al-Adawi S, Al-Yahyaee SA. Novel mutation of GLRA1 in Omani families with hyperekplexia and mild mental retardation. Pediatr Neurol. 2012;46(2):89–93. doi: 10.1016/j.pediatrneurol.2011.11.008. - DOI - PubMed

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A de novo CTNNB1 nonsense mutation associated with syndromic atypical hyperekplexia, microcephaly and intellectual disability: a case report

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A de novo CTNNB1 nonsense mutation associated with syndromic atypical hyperekplexia, microcephaly and intellectual disability: a case report

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