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. 2022 Jun;24(6):1261-1273.
doi: 10.1016/j.gim.2022.02.013. Epub 2022 Mar 24.

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

Reem Al-Jawahiri  1 , Aidin Foroutan  2 , Jennifer Kerkhof  2 , Haley McConkey  2 , Michael Levy  2 , Sadegheh Haghshenas  2 , Kathleen Rooney  2 , Jasmin Turner  3 , Debbie Shears  4 , Muriel Holder  5 , Henrietta Lefroy  6 , Bruce Castle  6 , Linda M Reis  7 , Elena V Semina  7 ; University of Washington Centre for Mendelian Genomics (UW-CMG); Katherine Lachlan  8 , Kate Chandler  9 , Thomas Wright  9 , Jill Clayton-Smith  9 , Franziska Phan Hug  10 , Nelly Pitteloud  10 , Lucia Bartoloni  10 , Sabine Hoffjan  11 , Soo-Mi Park  12 , Ajay Thankamony  12 , Melissa Lees  13 , Emma Wakeling  13 , Swati Naik  14 , Britta Hanker  15 , Katta M Girisha  16 , Emanuele Agolini  17 , Zampino Giuseppe  18 , Ziegler Alban  19 , Marine Tessarech  19 , Boris Keren  20 , Alexandra Afenjar  20 , Christiane Zweier  21 , Andre Reis  21 , Thomas Smol  22 , Yoshinori Tsurusaki  23 , Okamoto Nobuhiko  24 , Futoshi Sekiguchi  25 , Naomi Tsuchida  25 , Naomichi Matsumoto  25 , Ikuyo Kou  26 , Yoshiro Yonezawa  27 , Shiro Ikegawa  26 , Bert Callewaert  28 , Megan Freeth  1 ; Genomics England Research Consortium; Lotte Kleinendorst  29 , Alan Donaldson  30 , Marielle Alders  31 , Anne De Paepe  32 , Bekim Sadikovic  33 , Alisdair McNeill  34
Collaborators, Affiliations

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

Reem Al-Jawahiri et al. Genet Med. 2022 Jun.

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.

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Conflict of interest statement

Conflict of Interest The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Schematic diagram of reported SOX11 variants.
Illustration of missense and protein truncating variants in SOX11 in people with neurodevelopmental disorders. Both novel variants identified in this study and those identified in published patients are shown. The black box indicates the high-mobility group domain. The domain is not drawn to scale. Domain boundaries (amino acid number) as defined by Refseq (NP_003099.1), SwissProt (P35716.2), and International Nucleotide Sequence Database Collaboration (AAB08518.1). TAD, transactivating domain. Refseq, National Center for Biotechnology Information Reference Sequence Database.
Figure 2
Figure 2. Assessment of SOX11 variant impact on transactivation of target gene.
A. Western blot showing lower molecular weight of G384Rfs*14 and Y294* SOX11 variants than that of WT SOX11 protein. An anti-FLAG M2 HRP antibody (1:3000; Sigma-Aldrich) was used. B. Luciferase assay showing impaired activation of GDF5 promotor by G384Rfs*14 and Y294* SOX11 variants. A176E impairs SOX11 activity but to a much lesser extent than Y294* or G384Rfs*14. Data were taken from 2 separate experiments; each experiment was performed in technical triplicate. Activation of GDF5 promotor was compared between WT SOX11 protein and 3 SOX11 variants (G384Rfs*14, A176E, and Y294*) using t test. Correction for multiple comparisons was undertaken with a P value of .016 being taken as significant (0.5/3 = .016). WT, wild type.
Figure 3
Figure 3. MVP scores plot.
A. MVP scores was created using the support vector machine (SVM) trained by comparing 10 SOX11 samples against controls. B. MVP scores were created using the SVM trained by comparing 10 SOX11 samples against controls and 38 neurodevelopmental disorders and congenital anomalies available in the EpiSign Knowledge Database. The blue circles represent the training samples, and the gray circles represent the testing samples. MVP, methylation variant pathogenicity.
Figure 4
Figure 4. Phenotype-based clustering analysis of SOX11 and ARID1B phenotypes.
Hierarchical cluster analysis was performed in Python. Euclidean distance and Ward parameters were used to compute linkage distance and cluster merge strategy. SOX11 and ARID1B variant heterozygotes lie in different clusters. OFC indicates OFC < 2 SD. Coarse indicates coarse facial features. Structural eye indicates structural eye disease. Subs indicates individual subject. IHH, idiopathic hypogonadism; OFC, orbitofrontal circumference; OMA, oculomotor apraxia.
Figure 5
Figure 5. RNAscope images of SOX11 expression using probes to SOX11.
A. Saggital image of Carnegie stage (CS) 21 (CS21) (around 51 days after conception, 2× magnification). Note, diffused staining in central nervous system (red signal). SOX11 expression in frontal cortex (*), spinal cord (**), and palate (***). SOX11 probe is labeled red. No counterstain was used. B. SOX11 expression in developing eye at CS23 (around 56 days after conception, 4×) in lens (*), optic nerve (**), and neuroretina (***). SOX11 probe is labeled red. No counterstain was used. C. SOX11 expression in pituitary at CS20 (around 49 days after conception, 10×) lining lumen of adenohypophysis (*) and also in neurohypophysis (**). SOX11 probe is labeled red. No counterstain was used.
See this image and copyright information in PMC

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