Phenotypic expansion in Zhu‐Tokita‐Takenouchi‐Kim syndrome caused by de novo variants in the SON gene

• Published in: Molecular genetics & genomic medicine Vol. 8; no. 10; pp. e1432 - n/a
• Main Authors: Slezak, Ryszard, Smigiel, Robert, Rydzanicz, Malgorzata, Pollak, Agnieszka, Kosinska, Joanna, Stawinski, Piotr, Malgorzata Sasiadek, Maria, Ploski, Rafal
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.10.2020; John Wiley and Sons Inc; Wiley
• Subjects: Amino acids; Birth weight; Cell adhesion & migration; Child development; Clinical Report; Clinical Reports; Criteria; Deoxyribonucleic acid; Diagnosis; Diagnostic systems; DNA; DNA sequencing; Etiology; Families & family life; Hypotonia; Immunoglobulin A; Intellectual disabilities; intellectual disability; Intestine; Medical screening; Mutation; Nose; Nucleotide sequence; Parents & parenting; Patients; Point mutation; Proteins; psychomotor delay; Respiratory tract; Respiratory tract diseases; Seizures; Signs and symptoms; SON gene; Strabismus; Ultrasonic imaging; Zhu‐Tokita‐Takenouchi‐Kim syndrome; United States > US; SON gene; Zhu-Tokita-Takenouchi-Kim syndrome; psychomotor delay; intellectual disability
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.1432

Background The genetic etiology of intellectual and psychomotor disability without a defined spectrum of dysmorphic features is usually monogenic. As no diagnostic criteria for such diseases are established, the clinical diagnosis becomes to be a challenge. The object of our paper is to present two patients with non‐specific clinical symptoms for whom whole‐exome‐sequencing identified the new SON mutations and thus allowed for establishing the diagnosis of Zhu‐Tokita‐Takenouchi‐Kim (ZTTK) syndrome. In both patients, the same symptoms including hypotonia, developmental and speech delay, feeding difficulties as well as frequent infections of the respiratory tract and internal ear were observed. However, both cases presented also with exceptional symptoms such as in case 1 ventriculomegaly and asymmetry of ventricles, hypoplastic left heart syndrome (HLHS), intellectual disability, intestinal malrotation, gastroparesis, and duodenal atresia and in the case 2 febrile seizures and reduced IgA levels. We will be presenting the patients and comparing them to 30 previously described cases. Methods Whole‐exome sequencing (WES) was performed on the probands’ DNA and paired‐end sequenced (2x100 bp) on HiSeq 1500. Variants considered as disease‐causing were validated in the proband and studied in all available family members by amplicon deep sequencing performed using Nextera XT Kit and sequenced on HiSeq 1500. Results We have identified two new variants in SON gene. In case 1 it has been a heterozygous frameshift variant p.(Ala1340GlnfsTer26), while in case 2 it has been a heterozygous frameshift variant, p.(Asp1640GlyfsTer7). Both variants are described for the first time and up to now, are not mentioned in any database. Conclusion As there are no precise criteria established for the clinical diagnosis of ZTTK, an identification of SON gene mutation by whole‐exome‐sequencing is the best method that allows for a diagnosis of this syndrome. In the paper, we present both, clinical symptoms as well as newly identified SON variants in our two patients with Zhu‐Tokita‐Takenouchi‐Kim syndrome in relation to clinical and molecular alterations in 30 cases described up to now.