Novel compound heterozygous variants of the SEC23A gene in a Chinese family with cranio-lenticulo-sutural dysplasia based on data from a large cohort of congenital cataract patients

Abstract

Background Cranio-lenticulo-sutural dysplasia (CLSD) is a rare dysmorphic syndrome characterized by skeletal dysmorphism, late-closing fontanels, and cataracts. CLSD is caused by mutations in the SEC23A gene (OMIM# 607812) and can be inherited in either an autosomal dominant or autosomal recessive pattern. To date, only four mutations have been reported to cause CLSD. This study aims to identify the disease-causing variants in a large cohort of congenital cataract patients, to expand the genotypic and phenotypic spectrum of CLSD, and to confirm the association between SEC23A and autosomal recessive CLSD (ARCLSD). Methods We collected detailed medical records and performed comprehensive ocular examinations and whole-exome sequencing (WES) on 115 patients with congenital cataracts. After suspecting that a patient may have CLSD based on the sequencing results, we proceeded to conduct transmission electron microscopy (TEM) on the cultured skin fibroblasts. The clinical validity of the reported gene-disease relationships for the gene and the disease was evaluated using the ClinGen gene curation framework. Results Two novel compound heterozygous variants (c.710A > C p.Asp237Ala, c.1946T > C p.Leu649Pro) of the SEC23A gene, classified as variant of uncertain significance, were identified in the proband with skeletal, cardiac, ocular, and hearing defects. The observation of typical distended endoplasmic reticulum cisternae further supported the diagnosis of CLSD. Application of the ClinGen gene curation framework confirmed the association between SEC23A and ARCLSD. Conclusion This study expands the genotypic and phenotypic spectrum of CLSD, proposes TEM as a supplemental diagnostic method, and indicates that congenital cataracts are a typical sign of ARCLSD.

First Case of a Dominant De Novo SEC23A Mutation with Neurological and Psychiatric Features: New Insights into Cranio-Lenticulo-Sutural Dysplasia with Literature Review

“…This suggests that missense variants may play a pivotal role in the pathogenesis of CLSD, influencing the structure and, subsequently, the function of SEC23A, impacting its interaction with other proteins within the COPII complex. Moreover, in AR-CLSD forms, the variants in SEC23A affect the early exons of the gene (except for patient 5 who is a compound heterozygous [18]) while, in AD-CLSD forms, they are present in the last exons of the gene. This clustering of variants, which occurs differently according to the inheritance of CLSD, suggests that the SEC23A gene could account for two different forms of syndrome with common features but different clinical outcomes.…”

“…Among the eight cases already reported in the literature with mutations in the SEC23A gene, four patients were described with the homozygous missense variant p.Phe382Leu [1], one patient harbored the heterozygous missense variant p.Met702Val [7], two patients had the heterozygous missense variant p.Glu599Lys [4], and one patient harbored the two missense variants p.Asp237Ala and p.Leu649Pro in compound heterozygosity [18]. We have grouped the main features of these nine patients (the eight patients present in the literature and our patient) into five groups according to phenotypic and neuropsychiatric criteria using the standardized terms of Human Phenotype (HP) Ontology [19]: head abnormalities (HP:0000234), eye abnormalities (HP:0000478), facial abnormalities (HP:0000271), growth delay (HP:0001510), and abnormalities in nervous system function (HP:0012638).…”

“…Concerning growth delay, proportionate short stature (HP:0003508) is observed in all the patients except for patient 5 because the authors focused on the ophthalmologic aspects and not on weight-stature balance [18]. The presence of growth delay needs to be meticulously evaluated and monitored by clinicians who approach children affected by CLSD.…”