Rare novel variants in the ZIC3 gene cause X-linked heterotaxy

Aimee D C Paulussen; Anja Steyls; Jo Vanoevelen; Florence Hj van Tienen; Ingrid P C Krapels; Godelieve Rf Claes; Sonja Chocron; Crool Velter; Gita M Tan-Sindhunata; Catarina Lundin; Irene Valenzuela; Balint Nagy; Iben Bache; Lisa Leth Maroun; Kristiina Avela; Han G Brunner; Hubert J M Smeets; Jeroen Bakkers; Arthur van den Wijngaard

doi:10.1038/ejhg.2016.91

Rare novel variants in the ZIC3 gene cause X-linked heterotaxy

Aimee D C Paulussen, Anja Steyls, Jo Vanoevelen, Florence Hj van Tienen, Ingrid P C Krapels, Godelieve Rf Claes, Sonja Chocron, Crool Velter, Gita M Tan-Sindhunata, Catarina Lundin, Irene Valenzuela, Balint Nagy, Iben Bache, Lisa Leth Maroun, Kristiina Avela, Han G Brunner, Hubert J M Smeets, Jeroen Bakkers, Arthur van den Wijngaard

Medical Genetics Program

9 Citations (Scopus)

Abstract

Variants in the ZIC3 gene are rare, but have demonstrated their profound clinical significance in X-linked heterotaxy, affecting in particular male patients with abnormal arrangement of thoracic and visceral organs. Several reports have shown relevance of ZIC3 gene variants in both familial and sporadic cases and with a predominance of mutations detected in zinc-finger domains. No studies so far have assessed the functional consequences of ZIC3 variants in an in vivo model organism. A study population of 348 patients collected over more than 10 years with a large variety of congenital heart disease including heterotaxy was screened for variants in the ZIC3 gene. Functional effects of three variants were assessed both in vitro and in vivo in the zebrafish. We identified six novel pathogenic variants (1,7%), all in either male patients with heterotaxy (n=5) or a female patient with multiple male deaths due to heterotaxy in the family (n=1). All variants were located within the zinc-finger domains or leading to a truncation before these domains. Truncating variants showed abnormal trafficking of mutated ZIC3 proteins, whereas the missense variant showed normal trafficking. Overexpression of wild-type and mutated ZIC protein in zebrafish showed full non-functionality of the two frame-shift variants and partial activity of the missense variant compared with wild-type, further underscoring the pathogenic character of these variants. Concluding, we greatly expanded the number of causative variants in ZIC3 and delineated the functional effects of three variants using in vitro and in vivo model systems.

Original language	English
Journal	European Journal of Human Genetics
Volume	24
Issue number	12
Pages (from-to)	1783-1791
Number of pages	9
ISSN	1018-4813
DOIs	https://doi.org/10.1038/ejhg.2016.91
Publication status	Published - 1 Dec 2016

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Paulussen, A. D. C., Steyls, A., Vanoevelen, J., van Tienen, F. H., Krapels, I. P. C., Claes, G. R., Chocron, S., Velter, C., Tan-Sindhunata, G. M., Lundin, C., Valenzuela, I., Nagy, B., Bache, I., Maroun, L. L., Avela, K., Brunner, H. G., Smeets, H. J. M., Bakkers, J., & van den Wijngaard, A. (2016). Rare novel variants in the ZIC3 gene cause X-linked heterotaxy. European Journal of Human Genetics, 24(12), 1783-1791. https://doi.org/10.1038/ejhg.2016.91

Paulussen, ADC, Steyls, A, Vanoevelen, J, van Tienen, FH, Krapels, IPC, Claes, GR, Chocron, S, Velter, C, Tan-Sindhunata, GM, Lundin, C, Valenzuela, I, Nagy, B, Bache, I, Maroun, LL, Avela, K, Brunner, HG, Smeets, HJM, Bakkers, J & van den Wijngaard, A 2016, 'Rare novel variants in the ZIC3 gene cause X-linked heterotaxy', European Journal of Human Genetics, vol. 24, no. 12, pp. 1783-1791. https://doi.org/10.1038/ejhg.2016.91

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title = "Rare novel variants in the ZIC3 gene cause X-linked heterotaxy",

abstract = "Variants in the ZIC3 gene are rare, but have demonstrated their profound clinical significance in X-linked heterotaxy, affecting in particular male patients with abnormal arrangement of thoracic and visceral organs. Several reports have shown relevance of ZIC3 gene variants in both familial and sporadic cases and with a predominance of mutations detected in zinc-finger domains. No studies so far have assessed the functional consequences of ZIC3 variants in an in vivo model organism. A study population of 348 patients collected over more than 10 years with a large variety of congenital heart disease including heterotaxy was screened for variants in the ZIC3 gene. Functional effects of three variants were assessed both in vitro and in vivo in the zebrafish. We identified six novel pathogenic variants (1,7%), all in either male patients with heterotaxy (n=5) or a female patient with multiple male deaths due to heterotaxy in the family (n=1). All variants were located within the zinc-finger domains or leading to a truncation before these domains. Truncating variants showed abnormal trafficking of mutated ZIC3 proteins, whereas the missense variant showed normal trafficking. Overexpression of wild-type and mutated ZIC protein in zebrafish showed full non-functionality of the two frame-shift variants and partial activity of the missense variant compared with wild-type, further underscoring the pathogenic character of these variants. Concluding, we greatly expanded the number of causative variants in ZIC3 and delineated the functional effects of three variants using in vitro and in vivo model systems.",

author = "Paulussen, {Aimee D C} and Anja Steyls and Jo Vanoevelen and {van Tienen}, {Florence Hj} and Krapels, {Ingrid P C} and Claes, {Godelieve Rf} and Sonja Chocron and Crool Velter and Tan-Sindhunata, {Gita M} and Catarina Lundin and Irene Valenzuela and Balint Nagy and Iben Bache and Maroun, {Lisa Leth} and Kristiina Avela and Brunner, {Han G} and Smeets, {Hubert J M} and Jeroen Bakkers and {van den Wijngaard}, Arthur",

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AU - Krapels, Ingrid P C

AU - Claes, Godelieve Rf

AU - Chocron, Sonja

AU - Velter, Crool

AU - Tan-Sindhunata, Gita M

AU - Lundin, Catarina

AU - Valenzuela, Irene

AU - Nagy, Balint

AU - Bache, Iben

AU - Maroun, Lisa Leth

AU - Avela, Kristiina

AU - Brunner, Han G

AU - Smeets, Hubert J M

AU - Bakkers, Jeroen

AU - van den Wijngaard, Arthur

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N2 - Variants in the ZIC3 gene are rare, but have demonstrated their profound clinical significance in X-linked heterotaxy, affecting in particular male patients with abnormal arrangement of thoracic and visceral organs. Several reports have shown relevance of ZIC3 gene variants in both familial and sporadic cases and with a predominance of mutations detected in zinc-finger domains. No studies so far have assessed the functional consequences of ZIC3 variants in an in vivo model organism. A study population of 348 patients collected over more than 10 years with a large variety of congenital heart disease including heterotaxy was screened for variants in the ZIC3 gene. Functional effects of three variants were assessed both in vitro and in vivo in the zebrafish. We identified six novel pathogenic variants (1,7%), all in either male patients with heterotaxy (n=5) or a female patient with multiple male deaths due to heterotaxy in the family (n=1). All variants were located within the zinc-finger domains or leading to a truncation before these domains. Truncating variants showed abnormal trafficking of mutated ZIC3 proteins, whereas the missense variant showed normal trafficking. Overexpression of wild-type and mutated ZIC protein in zebrafish showed full non-functionality of the two frame-shift variants and partial activity of the missense variant compared with wild-type, further underscoring the pathogenic character of these variants. Concluding, we greatly expanded the number of causative variants in ZIC3 and delineated the functional effects of three variants using in vitro and in vivo model systems.

AB - Variants in the ZIC3 gene are rare, but have demonstrated their profound clinical significance in X-linked heterotaxy, affecting in particular male patients with abnormal arrangement of thoracic and visceral organs. Several reports have shown relevance of ZIC3 gene variants in both familial and sporadic cases and with a predominance of mutations detected in zinc-finger domains. No studies so far have assessed the functional consequences of ZIC3 variants in an in vivo model organism. A study population of 348 patients collected over more than 10 years with a large variety of congenital heart disease including heterotaxy was screened for variants in the ZIC3 gene. Functional effects of three variants were assessed both in vitro and in vivo in the zebrafish. We identified six novel pathogenic variants (1,7%), all in either male patients with heterotaxy (n=5) or a female patient with multiple male deaths due to heterotaxy in the family (n=1). All variants were located within the zinc-finger domains or leading to a truncation before these domains. Truncating variants showed abnormal trafficking of mutated ZIC3 proteins, whereas the missense variant showed normal trafficking. Overexpression of wild-type and mutated ZIC protein in zebrafish showed full non-functionality of the two frame-shift variants and partial activity of the missense variant compared with wild-type, further underscoring the pathogenic character of these variants. Concluding, we greatly expanded the number of causative variants in ZIC3 and delineated the functional effects of three variants using in vitro and in vivo model systems.

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DO - 10.1038/ejhg.2016.91

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SP - 1783

EP - 1791

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 12

ER -

Rare novel variants in the ZIC3 gene cause X-linked heterotaxy

Abstract

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