Identification of a Rare Branch Point Variant in the
SMS Gene in a Large Family With a Severe Form of
Snyder–Robinson Syndrome

Antoine Civit, Nathalie Ronce, Benjamin Cogné, Thomas Besnard, David Laurenceau, Catherine Hubert, Marie-pierre Moizard, Paul Gueguen, Annick Toutain, Marie-laure Vuillaume

► To cite this version:

Antoine Civit, Nathalie Ronce, Benjamin Cogné, Thomas Besnard, David Laurenceau, et al.. Identification of a Rare Branch Point Variant in the SMS Gene in a Large Family With a Severe Form of Snyder-Robinson Syndrome. Clinical Genetics, 2024, 107 (2), pp.231 - 233. 10.1111/cge.14643. hal-05115884

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RESEARCH LETTER

OPEN ACCESS

# Identification of a Rare Branch Point Variant in the SMS Gene in a Large Family With a Severe Form of Snyder–Robinson Syndrome

Antoine Civit<fnref n="1" /> | Nathalie Ronce<fnref n="1" /> | Benjamin Cogné²,³ | Thomas Besnard²,³ | David Laurenceau<fnref n="1" /> | Catherine Hubert<fnref n="1" /> | Marie-Pierre Moizard<fnref n="1" /> | Paul Gueguen<fnref n="1" />,⁴ | Annick Toutain<fnref n="1" />,⁴ | Marie-Laure Vuillaume<fnref n="1" />,⁴

**Correspondence:** Marie-Laure Vuillaume (m.winter@chu-tours.fr)

**Received:** 20 September 2024 | **Revised:** 21 October 2024 | **Accepted:** 24 October 2024

**Keywords:** branch point variant | RNA-Seq | SMS | Snyder–Robinson syndrome

To the Editor,

Snyder–Robinson syndrome (SRS) is a rare X-linked recessive syndrome characterized by intellectual disability, speech abnormalities, epilepsy, osteoporosis, low muscle bulk, and dysmorphic features and caused by hemizygous loss-of-function variants in the SMS gene.

In 1999, our group reported a large X-linked intellectual disability French family with hypotonia, severe early-onset seizures, muscle hypodevelopment, bone demineralization, and dysmorphic craniofacial features, which retrospectively fits with SRS (Figure 1A) [1]. Informed consents signed by legal guardians and/or patients for genetic studies were obtained. Linkage analysis highlighted a 11.2 Mb candidate region in the Xp proximal region (Xp22.13-Xp21.2) but subsequent X-exome sequencing failed to identify the causative gene. Recently, we identified by exome sequencing in the proband a hemizygous branch point (BP) variant NM_004595.5(SMS):c.661-13A>C inherited from the healthy mother, in the intron 6 of the SMS gene (Figure 1B). This variant, located within the linkage region, segregated with the disease in this family and was predicted to affect the BP motif relevant for physiological SMS pre-mRNA splicing (Figure 1B). BP variants may compromise the assembly of the spliceosome, leading to dramatic changes in splicing and gene expression with disease consequences. BPs are difficult to identify in the human genome as their surrounding sequences show

high degeneracy. Until now, only few diseases caused by BP mutations have been described and in most cases, these BP variants result in complete/partial exon skipping or intron retention or a combination of both [2].

RT-PCR analysis conducted on patient's mRNA showed a predicted 205 bp fragment containing SMS wild-type mRNA and two additional mRNA fragments measuring approximately 250 and 1000 bp in the proband (Figure 1C). Exome targeted RNA-seq data only showed the presence of a predominant aberrant transcript with a complete inclusion of intron 6, probably corresponding to the longest abnormal fragment detected by RT-PCR. Due to intron retention, this aberrant transcript could escape NMD by being temporally sequestered in the nucleus, as it was suggested in some studies focusing on transcripts with retained introns.

Until now, 32 hemizygous pathogenic variants have been described in both literature, ClinVar and DECIPHER databases including 26 different missense variants, one nonsense variant, three splice variants and two frameshift variants (Figure 1E) [3–5]. In the previously reported SRS patients, there is a wide phenotypic variability and most of the variants described so far, are hypomorphic missense variants affecting protein folding and dimerization and probably resulting in reduced spermine synthase activity. Only one hemizygous truncating variant was

<footnote n="1">¹Service de Génétique, Centre Hospitalier Régional Universitaire de Tours, Tours, France | ²Nantes Université, CHU de Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France | ³Nantes Université, CHU de Nantes, Service de Génétique médicale, Nantes, France | ⁴UMR 1253, iBrain, Université de Tours, INSERM, Tours, France</footnote>

<footnote>The first two authors contributed equally to this article.</footnote>

<footnote>This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</footnote>

<footnote>© 2024 The Author(s). *Clinical Genetics* published by John Wiley & Sons Ltd.</footnote>
A.

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B.

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C.

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D.

<figure><img src="image_6.png" /></figure>

E.

<figure><img src="image_7.png" /><figcaption>**FIGURE 1** | (A) Partial pedigree of the family. (B) Overview of the region encompassing the SMS variant (Alamut Visual Plus software). (C) RT-PCR products using primers spanning exon 6–8 of SMS. (D) Sashimi plot from Integrative Genome Viewer (IGV) of exome targeted RNA-seq data. (E) SMS variants reported in the literature or in ClinVar and DECIPHER databases (upper and lower panel).</figcaption></figure>
associated with a total absence of the protein. This variant, iden-
tified in a male patient deceased at 4 months of age because of
severe multiple congenital anomalies, was suggested to lead to
the most severe form of the disease [3]. By comparison, the less
severe, and typical of SRS, phenotype observed in the affected
individuals of our family, could be explained by the presence of
a very small amount of the wild type transcript leading to a low
residual activity of the protein. Unfortunately, we were not able
to measure the spermine synthase activity in the patient's cell
nor determine if this variant was associated with a residual pres-
ence of SMS protein.

In conclusion, we have identified a novel variant in *SMS* which disrupts a predicted BP leading to a complete retention of intron 6. To our knowledge, this is the first report of a mutation that disrupts a functional BP sequence in SRS. Our results suggest that the phenotype observed in this family is caused by aberrant splicing of the *SMS* gene. This study also brings the end to the diagnostic course of this family, allowing appropriate genetic counseling to the new generations and emphasizes the importance of focusing on noncoding regions to improve molecular diagnosis.

**Conflicts of Interest**

The authors declare no conflicts of interest.

**Data Availability Statement**

Research data are not shared.

**References**

1. N. Ronce, M. Raynaud, A. Toutain, et al., “Evidence for a New X-Linked Mental Retardation Gene in Xp21-Xp22: Clinical and Molecular Data in One Family,” *American Journal of Medical Genetics* 83, no. 2 (1999): 132–137, https://doi.org/10.1002/(sici)1096-8628(19990312)83:2<132::aid-ajmg9>3.0.co;2-y.

2. P. Zhang, Q. Philippot, W. Ren, et al., “Genome-Wide Detection of Human Variants That Disrupt Intronic Branchpoints,” *Proceedings of the National Academy of Sciences of the United States of America* 119, no. 44 (2022): e2211194119, https://doi.org/10.1073/pnas.2211194119.

3. M. Leung, M. Sanchez-Castillo, N. Belnap, et al., “Snyder-Robinson Syndrome Presenting With Learning Disability, Epilepsy, and Osteoporosis: A Novel SMS Gene Variant,” *Rare* 2 (2024): 100017, https://doi.org/10.1016/j.rare.2023.100017.

4. A. L. Cason, Y. Ikeguchi, C. Skinner, et al., “X-Linked Spermine Synthase Gene (SMS) Defect: The First Polyamine Deficiency Syndrome,” *European Journal of Human Genetics* 11, no. 12 (2003): 937–944, https://doi.org/10.1038/sj.ejhg.5201072.

5. Y. Peng, J. Norris, C. Schwartz, and E. Alexov, “Revealing the Effects of Missense Mutations Causing Snyder-Robinson Syndrome on the Stability and Dimerization of Spermine Synthase,” *International Journal of Molecular Sciences* 17, no. 1 (January 2016): 77, https://doi.org/10.3390/ijms17010077.