SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile

Reem Al-Jawahiri; Aidin Foroutan; Jennifer Kerkhof; Haley McConkey; Michael Levy; Sadegheh Haghshenas; Kathleen Rooney; Jasmin Turner; Debbie Shears; Muriel Holder; Henrietta Lefroy; Bruce Castle; Linda M. Reis; Elena V. Semina; University of Washington Centre for Mendelian Genomics (UW-CMG); Deborah Nickerson; Michael Bamshad; Suzanne Leal; Katherine Lachlan; Kate Chandler; Thomas Wright; Jill Clayton-Smith; Franziska Phan Hug; Nelly Pitteloud; Lucia Bartoloni; Sabine Hoffjan; Soo Mi Park; Ajay Thankamony; Melissa Lees; Emma Wakeling; Swati Naik; Britta Hanker; Katta M. Girisha; Emanuele Agolini; Zampino Giuseppe; Ziegler Alban; Marine Tessarech; Boris Keren; Alexandra Afenjar; Christiane Zweier; Andre Reis; Thomas Smol; Yoshinori Tsurusaki; Okamoto Nobuhiko; Futoshi Sekiguchi; Naomi Tsuchida; Naomichi Matsumoto; Ikuyo Kou; Yoshiro Yonezawa; Shiro Ikegawa; Bert Callewaert; Megan Freeth; Genomics England Research Consortium; Lotte Kleinendorst; Alan Donaldson; Marielle Alders; Anne De Paepe; Bekim Sadikovic; Alisdair McNeill

doi:10.1016/j.gim.2022.02.013

SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile

Reem Al-Jawahiri, Aidin Foroutan, Jennifer Kerkhof, Haley McConkey, Michael Levy, Sadegheh Haghshenas, Kathleen Rooney, Jasmin Turner, Debbie Shears, Muriel Holder, Henrietta Lefroy, Bruce Castle, Linda M. Reis, Elena V. Semina, University of Washington Centre for Mendelian Genomics (UW-CMG), Deborah Nickerson, Michael Bamshad, Suzanne Leal, Katherine Lachlan, Kate ChandlerThomas Wright, Jill Clayton-Smith, Franziska Phan Hug, Nelly Pitteloud, Lucia Bartoloni, Sabine Hoffjan, Soo Mi Park, Ajay Thankamony, Melissa Lees, Emma Wakeling, Swati Naik, Britta Hanker, Katta M. Girisha, Emanuele Agolini, Zampino Giuseppe, Ziegler Alban, Marine Tessarech, Boris Keren, Alexandra Afenjar, Christiane Zweier, Andre Reis, Thomas Smol, Yoshinori Tsurusaki, Okamoto Nobuhiko, Futoshi Sekiguchi, Naomi Tsuchida, Naomichi Matsumoto, Ikuyo Kou, Yoshiro Yonezawa, Shiro Ikegawa, Bert Callewaert, Megan Freeth, Genomics England Research Consortium, Lotte Kleinendorst, Alan Donaldson, Marielle Alders, Anne De Paepe, Bekim Sadikovic^*, Alisdair McNeill^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

1 Downloads (Pure)

Abstract

Purpose: This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants. Methods: Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope. Results: We reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies. Conclusion: SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies.

Original language	English
Pages (from-to)	1261-1273
Number of pages	13
Journal	Genetics in Medicine
Volume	24
Issue number	6
Early online date	24 Mar 2022
DOIs	https://doi.org/10.1016/j.gim.2022.02.013
Publication status	Published - 1 Jun 2022
Externally published	Yes

Keywords

Exome
Genome sequencing
Hypogonadism
Methylation
Neurodevelopmental disorder
SOX11

Access to Document

10.1016/j.gim.2022.02.013Licence: CC BY

1-s2.0-S1098360022006657-mainFinal published version, 2.08 MBLicence: CC BY

Cite this

Al-Jawahiri, R., Foroutan, A., Kerkhof, J., McConkey, H., Levy, M., Haghshenas, S., Rooney, K., Turner, J., Shears, D., Holder, M., Lefroy, H., Castle, B., Reis, L. M., Semina, E. V., University of Washington Centre for Mendelian Genomics (UW-CMG), Nickerson, D., Bamshad, M., Leal, S., Lachlan, K., ... McNeill, A. (2022). SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile. Genetics in Medicine, 24(6), 1261-1273. https://doi.org/10.1016/j.gim.2022.02.013

@article{e70f0a8972e040059a6cf2e9be820e3c,

title = "SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile",

abstract = "Purpose: This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants. Methods: Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope. Results: We reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies. Conclusion: SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies.",

keywords = "Exome, Genome sequencing, Hypogonadism, Methylation, Neurodevelopmental disorder, SOX11",

author = "Reem Al-Jawahiri and Aidin Foroutan and Jennifer Kerkhof and Haley McConkey and Michael Levy and Sadegheh Haghshenas and Kathleen Rooney and Jasmin Turner and Debbie Shears and Muriel Holder and Henrietta Lefroy and Bruce Castle and Reis, {Linda M.} and Semina, {Elena V.} and {University of Washington Centre for Mendelian Genomics (UW-CMG)} and Deborah Nickerson and Michael Bamshad and Suzanne Leal and Katherine Lachlan and Kate Chandler and Thomas Wright and Jill Clayton-Smith and Hug, {Franziska Phan} and Nelly Pitteloud and Lucia Bartoloni and Sabine Hoffjan and Park, {Soo Mi} and Ajay Thankamony and Melissa Lees and Emma Wakeling and Swati Naik and Britta Hanker and Girisha, {Katta M.} and Emanuele Agolini and Zampino Giuseppe and Ziegler Alban and Marine Tessarech and Boris Keren and Alexandra Afenjar and Christiane Zweier and Andre Reis and Thomas Smol and Yoshinori Tsurusaki and Okamoto Nobuhiko and Futoshi Sekiguchi and Naomi Tsuchida and Naomichi Matsumoto and Ikuyo Kou and Yoshiro Yonezawa and Shiro Ikegawa and Bert Callewaert and Megan Freeth and {Genomics England Research Consortium} and Lotte Kleinendorst and Alan Donaldson and Marielle Alders and {De Paepe}, Anne and Bekim Sadikovic and Alisdair McNeill",

year = "2022",

month = jun,

day = "1",

doi = "10.1016/j.gim.2022.02.013",

language = "English",

volume = "24",

pages = "1261--1273",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier B.V.",

number = "6",

}

Al-Jawahiri, R, Foroutan, A, Kerkhof, J, McConkey, H, Levy, M, Haghshenas, S, Rooney, K, Turner, J, Shears, D, Holder, M, Lefroy, H, Castle, B, Reis, LM, Semina, EV, University of Washington Centre for Mendelian Genomics (UW-CMG), Nickerson, D, Bamshad, M, Leal, S, Lachlan, K, Chandler, K, Wright, T, Clayton-Smith, J, Hug, FP, Pitteloud, N, Bartoloni, L, Hoffjan, S, Park, SM, Thankamony, A, Lees, M, Wakeling, E, Naik, S, Hanker, B, Girisha, KM, Agolini, E, Giuseppe, Z, Alban, Z, Tessarech, M, Keren, B, Afenjar, A, Zweier, C, Reis, A, Smol, T, Tsurusaki, Y, Nobuhiko, O, Sekiguchi, F, Tsuchida, N, Matsumoto, N, Kou, I, Yonezawa, Y, Ikegawa, S, Callewaert, B, Freeth, M, Genomics England Research Consortium, Kleinendorst, L, Donaldson, A, Alders, M, De Paepe, A, Sadikovic, B & McNeill, A 2022, 'SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile', Genetics in Medicine, vol. 24, no. 6, pp. 1261-1273. https://doi.org/10.1016/j.gim.2022.02.013

TY - JOUR

T1 - SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile

AU - Al-Jawahiri, Reem

AU - Foroutan, Aidin

AU - Kerkhof, Jennifer

AU - McConkey, Haley

AU - Levy, Michael

AU - Haghshenas, Sadegheh

AU - Rooney, Kathleen

AU - Turner, Jasmin

AU - Shears, Debbie

AU - Holder, Muriel

AU - Lefroy, Henrietta

AU - Castle, Bruce

AU - Reis, Linda M.

AU - Semina, Elena V.

AU - University of Washington Centre for Mendelian Genomics (UW-CMG)

AU - Nickerson, Deborah

AU - Bamshad, Michael

AU - Leal, Suzanne

AU - Lachlan, Katherine

AU - Chandler, Kate

AU - Wright, Thomas

AU - Clayton-Smith, Jill

AU - Hug, Franziska Phan

AU - Pitteloud, Nelly

AU - Bartoloni, Lucia

AU - Hoffjan, Sabine

AU - Park, Soo Mi

AU - Thankamony, Ajay

AU - Lees, Melissa

AU - Wakeling, Emma

AU - Naik, Swati

AU - Hanker, Britta

AU - Girisha, Katta M.

AU - Agolini, Emanuele

AU - Giuseppe, Zampino

AU - Alban, Ziegler

AU - Tessarech, Marine

AU - Keren, Boris

AU - Afenjar, Alexandra

AU - Zweier, Christiane

AU - Reis, Andre

AU - Smol, Thomas

AU - Tsurusaki, Yoshinori

AU - Nobuhiko, Okamoto

AU - Sekiguchi, Futoshi

AU - Tsuchida, Naomi

AU - Matsumoto, Naomichi

AU - Kou, Ikuyo

AU - Yonezawa, Yoshiro

AU - Ikegawa, Shiro

AU - Callewaert, Bert

AU - Freeth, Megan

AU - Genomics England Research Consortium

AU - Kleinendorst, Lotte

AU - Donaldson, Alan

AU - Alders, Marielle

AU - De Paepe, Anne

AU - Sadikovic, Bekim

AU - McNeill, Alisdair

PY - 2022/6/1

Y1 - 2022/6/1

N2 - Purpose: This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants. Methods: Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope. Results: We reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies. Conclusion: SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies.

AB - Purpose: This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants. Methods: Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope. Results: We reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies. Conclusion: SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies.

KW - Exome

KW - Genome sequencing

KW - Hypogonadism

KW - Methylation

KW - Neurodevelopmental disorder

KW - SOX11

UR - http://www.scopus.com/inward/record.url?scp=85127338633&partnerID=8YFLogxK

U2 - 10.1016/j.gim.2022.02.013

DO - 10.1016/j.gim.2022.02.013

M3 - Article

C2 - 35341651

AN - SCOPUS:85127338633

SN - 1098-3600

VL - 24

SP - 1261

EP - 1273

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 6

ER -

SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile

Abstract

Keywords

Access to Document

Other files and links

Cite this