Abstract
Introduction
Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare multisystemic congenital disorder caused by SON gene variants. This study aimed to present the results of whole exome sequencing, and describe some rare findings observed in the proband.
Case Presentation
An 11-year-old boy exhibited hypotonia, poor growth, short stature, and microcephaly. The patient displayed various neurological symptoms, such as developmental delay, seizures, hydrocephalus, and brain abnormalities. He presented with strabismus, urinary problems, and facial dysmorphism. A history of stroke, obsession, insomnia, self-injurious behavior, and hearing loss was also noted. Based on the patient’s clinical findings, whole exome sequencing was performed. A novel variant in the SON gene was identified. This variant was confirmed by Sanger sequencing. Notably, the parents tested normal for the variant.
Conclusion
This study presents a patient who exhibited a wide range of behavioral abnormalities, stroke, and recurrent urolithiasis – features that are rarely reported in ZTTK syndrome – and includes a review of the literature.
Keywords: Delins variant, Developmental delay, Intellectual disability, SON, Zhu-Tokita-Takenouchi-Kim syndrome
Established Facts
Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare multisystemic congenital disorder caused by pathogenic variants in the SON gene.
ZTTK syndrome is an autosomal dominant disorder characterized by developmental delay, intellectual disability, hypotonia, and multisystemic abnormalities.
To date, approximately 80 patients have been reported in the literature.
Novel Insights
A novel delins variant in the SON gene was identified in this study.
To the best of our knowledge, recurrent urolithiasis, as defined in our case, has not been reported as a clinical feature of this syndrome.
Introduction
Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome (OMIM #617140) is a rare multisystemic congenital disorder. Initially, in 2014 Gilissen et al. [1] reported a patient with intellectual disability caused by a variant in the SON. ZTTK syndrome was named after Tokita et al. [2], Takenouchi et al. [3], Kim et al. [4] who reported 28 unrelated patients in 2016, and 1 patient reported by Zhu et al. [5] in 2015. After these reports, this multisystem disorder was termed both ZTTK syndrome and “SON deficiency syndrome” because whole exome sequencing (WES) revealed that all the patients had variants in the SON gene [6].
ZTTK syndrome is an autosomal dominant disorder characterized by developmental delay, intellectual disability, hypotonia, and multisystemic abnormalities. Brain malformations and abnormal brain imaging, including thin corpus callosum, cortical and/or cerebellar atrophy, and alterations in cerebral cortical gyration, are commonly observed. Other clinical features include facial dysmorphism, musculoskeletal and visual abnormalities, hearing loss, and genitourinary, and heart defects. To date, approximately 80 patients have been reported in the literature. Most of the variants identified in the SON gene were of the frameshift type. Herein, we present a case study detailing a patient who not only exhibited findings essential for the diagnosis of ZTTK syndrome but also displayed rare manifestations and our study highlights a range of systemic findings as referred by a literature review.
Case Presentation
An 11-year-old boy, born to healthy, non-consanguineous parents during his mother’s second pregnancy, was referred to our outpatient clinic (Fig. 1a). The pregnancy was uneventful. He was first evaluated at 9 years and 10 months of age, presenting with global developmental delay, intellectual disability, hypotonia, and impaired overall growth. Developmental milestones were significantly delayed: he was able to sit without support at the age of 2, began crawling at age 3, and had not yet begun walking by age 10. On physical examination at 10 years and 3 months of age, he exhibited growth retardation, short stature, and microcephaly. His weight was 14 kg (−5.91 SD), height was 104 cm (−5.76 SD), and head circumference measured 49.5 cm (−2.85 SD). He had a long and flat face, two hair whorls, downslanting palpebral fissures, long eyelashes, low-hanging columella, prominent ears, dental crowding, enamel hypoplasia, an open mouth, persistent drolling, midface hypoplasia, prognathism, onycodystrophy, and hypoplasia of the toenails (Fig. 1b–e). He was diagnosed with noncommunicating hydrocephalus at the age of 4, and at 11 years old, he experienced two seizure episodes, which were controlled with levetiracetam treatment. Electrocardiograms and echocardiograms were normal. Additionally, he presented with strabismus, bilateral conductive hearing loss attributed to recurrent otitis media, and low immunoglobulin levels. Recurrent urolithiasis was noted, along with various behavioral abnormalities such as aggression, obsession, insomnia, and self-injurious behavior. Minimal scoliosis was observed on X-ray imaging, and brain MRI revealed thinning of the posterior part of the corpus callosum body and the presence of an arachnoid cyst in the left temporal anteromedial region of the brain (Fig. 1f–h). Metabolic parameter assessment indicated a slight elevation of ethylmalonic acid and dicarboxylic acid in urine organic acids, although the findings were nonspecific. Additionally, due to thrombocytosis, the patient experienced a stroke and was prescribed anticoagulants.
Fig. 1.
Pedigree of the family, dysmorphism, and radiological imaging of the patient. a The individual marked as (IV,2) on the pedigree is the propositus. b The patient had a long and flat face, downslanting palpebral fissures, long eyelashes, midface hypoplasia, low-hanging columella. c Prominent and large ears, prognathism. d Dental crowding, open mouth. e Onycodystrophy and hypoplasia of the toenails. f The arrow indicates partial thinning of the posterior body of the corpus callosum. g The arrow shows an arachnoid cyst on the left temporal anteromedial part of the brain. h X-ray examination revealed that there is minimal scoliosis in the upper thoracic region.
Methods
After obtaining informed consent from the parents of the patient, chromosomal analysis was performed using the G banding technique. Next, a comparative genomic hybridization microarray protocol provided by Agilent Sure G3 Human CGH Microarray in 8 × 60K resolution accompanied by databases including DECIPHER, UCSC Genome Browser, ISCA, ClinGen, OMIM, and PheGenI were applied. Low levels of mosaicism (<30%) and copy number changes below approximately 200 kb were not reported. The limit for filtering was 200 kb for copy number losses and 400 kb for gains. Subsequently, whole exome sequencing conducted on a trio consisting of a proband and both parents was carried out. The study was conducted by manufacturer’s (QIAGEN) protocol. The DNA was extracted from peripheral blood of the patient. Libraries were constructed using the QIAseq FX library kit, exome DNA enrichment was performed with the QIAseq Human Exome kit (QIAGEN), resultant amplified and cleaned libraries were then assessed for adapter dimers, yield and aberrant peaks using a QIAxcel (QIAGEN), paired-end 150 × 150 whole exome sequencing was performed using NovaSeq 6000 (Illumina) with the NovaSeq 6000 S2 Reagent Kit v1 (300 cycles). On the bioinformatic processing, demultiplexing and raw bcl files were converted to FASTQ format for further processing using a custom in-house built algorithm. FASTQ files were aligned to GRCh38 using a custom in-house workflow utilizing the CLC read mapper. After mapping reads to the reference genome (GRCh38), PCR duplicates were removed using the CLC Genomic Workbench’s (QIAGEN) Remove Duplicate Mapped Reads tool and variant calling was performed after local realignment using the Probabilistic Variant Caller tool of CLC Genomic Workbench (QIAGEN). Variants with <20% variant allele fraction, <20X Coverage and Phred-based quality score of Q25 were not included in the tertiary analysis. Inspection of read mapping was confirmed using Integrated Genomics Viewer (Broad Institute). Trio exome sequencing data for all samples were then analyzed for variants causative of the patient’s symptoms based on the molecular data and our clinical assessment. American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines were taken into account in the classification [7]. Protein function prediction software SIFT, MutationTaster, CADD, and PolyPhen were utilized to predict the protein function of the SON gene variant. Sanger sequencing was performed with the Applied Biosystems AB3500 Genetic Analyzer to confirm the variant. The results were compared with the reference gene sequence taken from the NCBI GenBank database and analyzed with the Mutation Surveyor program.
Results
No numerical or structural anomalies were detected by karyotyping (46,XY). The comparative genomic hybridization microarray test did not reveal any pathogenic copy number variants. Subsequently, whole exome sequencing was performed, and a novel variant, c.2145_2146delATinsTCTGGGG, p.A717Gfs*2, in the SON gene (NM_138927.4) was identified. This variant was confirmed by Sanger sequencing (Fig. 2). According to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, this variant meets the criteria for likely pathogenicity (PVS1, PM2). In silico tools such as SIFT, MutationTaster, CADD, and PolyPhen did not provide data regarding the effect of the variant on protein function. This delins variant results in the substitution of alanine at position 717 with glycine, leading to premature termination of the protein at two subsequent sites.
Fig. 2.
SON gene analysis of the patient. a The selected area represents the related DNA sequence of SON gene. b The consensus sequence of SON. c The arrow indicates the inserted nucleotides.
Discussion
ZTTK syndrome is an autosomal dominant multiorgan disorder resulting from haploinsufficiency of the SON gene. The manifestations of the disease encompass developmental delay, intellectual disability, hypotonia, heart defects, brain malformations, musculoskeletal abnormalities, vision and hearing impairments, abnormalities in ectoderm-derived tissues, behavioral problems, and urogenital and gastrointestinal malformations. Notably, all patients diagnosed with ZTTK syndrome exhibited developmental delay and intellectual disability [8, 9]. A majority of patients present with hypotonia, brain abnormalities, vision impairments, strabismus, skeletal abnormalities, and feeding difficulties during infancy. Nearly half of these patients exhibit short stature, low birth weight (<−2 SD), seizures, abnormalities of the corpus callosum, and urogenital malformations. Less than half of the patients experience microcephaly, autism spectrum disorder, respiratory and/or cardiac issues, abnormalities of the skin/hair/nails/teeth, immunological disorders, recurrent otitis media, craniosynostosis, hearing impairments, and macrocephaly (Table 1).
Table 1.
Clinical findings reported in patients diagnosed with ZTTK syndrome to date
| Clinical features | Kim et al. [4] (2016) | Tokita et al. [2] (2016) | Takenouchi et al. [3] (2016) | Kim et al. [6] (2019) | Yang et al. [10] (2019) | Quintana Castanedo et al. [11] (2020) | Yang and Yang [12] (2020) | Slezak et al. [13] (2020) | Tan et al. [14] (2020) | Peng et al. [15] (2021) | Dingemans et al. [16] (2022) | Kushary et al. [8] (2021) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Developmental delay | 20/20 | 7/7 | 1/1 | N/A | 1/1 | 1/1 | 1/1 | 2/2 | 1/1 | 1/1 | 18/18 | 15/15 |
| Intellectual disability | 20/20 | 7/7 | 1/1 | 1/1 | 1/1 | 1/1 | 1/1 | 2/2 | 1/1 | 1/1 | 15/16 | 15/15 |
| Hypotonia | 15/20 | 5/6 | 1/1 | N/A | N/A | 0/1 | 0/1 | 2/2 | 1/1 | 1/1 | 7/18 | 13/15 |
| Seizures | 11/20 | 4/6 | 0/1 | N/A | N/A | 1/1 | 1/1 | 1/2 | 0/1 | 1/1 | 8/18 | 9/15 |
| Brain malformations | 17/19 | 5/6 | 0/1 | N/A | 1/1 | 1/1 | 0/1 | 1/2 | 1/1 | 1/1 | 11/13 | 12/15 |
| Musculoskeletal abnormalities | 17/20 | 6/7 | 1/1 | N/A | 1/1 | 1/1 | 0/1 | 1/1 | 0/1 | 1/1 | 14/18 | 12/15 |
| Heart defects | 5/20 | 3/6 | 1/1 | N/A | 0/1 | 1/1 | 0/1 | 1/2 | 0/1 | 0/1 | 2/15 | 2/11 |
| Vision abnormalities | 15/20 | 5/7 | 0/1 | N/A | N/A | 1/1 | 0/1 | 2/2 | 0/1 | 1/1 | 10/18 | 7/12 |
| Hearing loss | 3/20 | 0/4 | 0/1 | N/A | 0/1 | 0/1 | N/A | 0/2 | 0/1 | 1/1 | 4/18 | 2/15 |
| Genitourinary abnormalities | 6/20 | 3/6 | 1/1 | 2/2 | 1/1 | 0/1 | 0/1 | 1/2 | 1/1 | 0/1 | 6/14 | 4/13 |
| Gastrointestinal abnormalities | 3/20 | 6/7 | 0/1 | N/A | 0/1 | 0/1 | 1/1 | 2/2 | 1/1 | 0/1 | 7/16 | 9/14 |
| Facial dysmorphism | 20/20 | 7/7 | 1/1 | N/A | 1/1 | 1/1 | 1/1 | 2/2 | 1/1 | 1/1 | 17/18 | 13/14 |
| Abnormalities of the skin/nails/hair/teeth | 3/20 | 2/7 | N/A | N/A | N/A | 1/1 | 1/1 | 1 | N/A | N/A | 11/16 | 4/15 |
| Behavioral problems | 5/20 | 4/5 | 0/1 | N/A | 0/1 | 0/1 | 1/1 | 2/2 | N/A | 1/1 | 16/17 | 3/15 |
| Clinical features | Yi et al. [17] (2022) | Pavone et al. [18] (2022) | Eid et al. [19] (2022) | Hudec et al. [20] (2022) | Tang et al. [9] (2023) | El-Said et al. [21] (2023) | Langford et al. [22] (2023) | Vasquez-Forero et al. [23] (2023) | Pietrobattista et al. [24] (2023) | Total | Percentage | Our case |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Developmental delay | 1/1 | 1/1 | 2/2 | 1/1 | 1/1 | 2/2 | 1/1 | 1/1 | 1/1 | 79/79 | 100% | + |
| Intellectual disability | 1/1 | 1/1 | 2/2 | 1/1 | 1/1 | 2/2 | 1/1 | 1/1 | 1/1 | 77/78 | 98.7% | + |
| Hypotonia | 1/1 | 1/1 | 2/2 | 1/1 | 1/1 | 2/2 | 1/1 | 1/1 | 0/1 | 55/77 | 71.4% | + |
| Seizures | 1/1 | 0/1 | 1/1 | 1/1 | 0/1 | 2/2 | 1/1 | 1/1 | N/A | 43/75 | 57.3% | − |
| Brain malformations | 1/1 | 1/1 | 2/2 | 1/1 | 1/1 | 2/2 | 1/1 | 1/1 | 1/1 | 61/72 | 84.7% | + |
| Musculoskeletal abnormalities | 0/1 | N/A | 0/2 | 1/1 | 0/1 | 2/2 | N/A | 1/1 | 1/1 | 59/76 | 77.6% | + |
| Heart defects | 0/1 | 0/1 | 0/2 | 1/1 | 0/1 | 1/1 | N/A | 0/1 | 0/1 | 17/69 | 24.6% | − |
| Eye abnormalities | 1/1 | 0/1 | 1/2 | N/A | 1 | 1/1 | N/A | 1/1 | 0/1 | 46/72 | 63.8% | + |
| Hearing loss | N/A | 0/1 | N/A | N/A | 1/1 | 1/1 | N/A | 0/1 | N/A | 12/68 | 17.6% | + |
| Genitourinary abnormalities | 0/1 | 0/1 | 0/2 | N/A | N/A | N/A | N/A | 1/1 | 1/1 | 27/69 | 39.1% | + |
| Gastrointestinal abnormalities | 0/1 | 0/1 | 2/2 | N/A | 1/1 | 1/1 | N/A | 1/1 | 1/1 | 35/73 | 47.9% | − |
| Facial dysmorphism | 1/1 | 1/1 | 2/2 | 1/1 | N/A | 2/2 | N/A | 1/1 | 1/1 | 74/76 | 97.3% | + |
| Abnormalities of the skin/nails/hair/teeth abnormalities | N/A | 1/1 | N/A | N/A | N/A | N/A | N/A | 0/1 | 0/1 | 24/65 | 36.9% | + |
| Behavioral problems | N/A | N/A | N/A | N/A | N/A | N/A | N/A | 1/1 | N/A | 33/65 | 50.7% | + |
The positivity rates reported in previous studies are summarized in the table.
N/A, not available.
Tokita et al. [2] identified a patient with ZTTK syndrome who presented with urolithiasis. However, to the best of our knowledge, recurrent urolithiasis, as defined in our case, has not been reported as a clinical feature of this syndrome. Mucocutaneous abnormalities, including retronychia and enamel hypoplasia, were initially described as findings of ZTTK syndrome by Castanedo et al. [11] in 2020. Our patient similarly exhibited dental abnormalities, enamel hypoplasia, onychodystrophy, and hypoplasia of the toenails which have rarely been reported in the literature to date [11, 23].
Yang and Yang [12] described a patient with severe maladjusted and destructive behavior, schizoid personality disorder, social withdrawal, maltreatment, and attention deficit hyperactivity disorder. Furthermore, various behavioral abnormalities were noted in additional patients as previously described [2, 4, 8, 13, 16, 23] (Table 1). Our patient presented with aggression, self-injurious behavior, insomnia, and obsession, thereby extending the range of behavioral issues observed in cases associated with ZTTK syndrome.
Additionally, stroke or transient hemiparesis/hemiplegia is rarely documented in ZTTK syndrome [2, 15, 21, 22]. However our patient exhibited left hemiplegia.
SON consists of 12 exons, with exon 3 constituting 82% of the entire coding region [15]. It plays a pivotal role in splicing short introns that have suboptimal weak splice sites and it is involved in both constitutive and alternative splicing [12]. The SON protein comprises 2,426 amino acids and its domains are distributed across 3 regions: an arginine/serine-rich domain, a G-patch domain, and a double-stranded RNA-binding motif [23]. It is localized in nuclear speckles and functions as a splicing cofactor contributing to cell cycle progression [23]. Knockdown of SON in HeLa and human embryonic stem cells leads to decreased expression of genes critical for neuronal cell migration, metabolism, mitochondrial function, and cell survival [12, 25].
Loss of function is a known mechanism underlying ZTTK syndrome. Exon 3, situated within the arginine-rich domain, serves as a hotspot region for genetic alterations. Notably, the c.5753_5756del variant, located within this exon and domain, is the most frequently observed alteration. Given that cardiac defects are more prevalent in patients harboring this variant, a potential genotype-phenotype correlation can be inferred [8].
Analysis of variants reported in the literature revealed that frameshift variants were the most prevalent type, accounting for 77.6% of cases, followed by nonsense (13.1%), missense (5.2%), and deletion variants (3.9%). The c.5753_5756del variant was the most frequently reported alteration, documented in 17 cases. Additionally, the c.3852_3856del, c.6010del, c.3334C>T, and c.1881_1882del variants were detected twice. Among all identified variants, 88.1% were found to be de novo, while the inheritance pattern of 11.8% remained unknown (Table 2).
Table 2.
Variants reported in patients with ZTTK syndrome to date
| Literature | cDNA | Protein | Mutation type | Inheritance |
|---|---|---|---|---|
| Gilissen et al. [1] (2014) | c.1881_1882del | p.Val629Alafs*56 | Frameshift | de novo |
| Zhu et al. [5] (2015) | c.5751_5754del | p.Val1918Glufs*87 | Frameshift | de novo |
| Tokita et al. [2] (2016) | c.5753_5756del | p.Val1918GlufsTer87 | Frameshift | de novo |
| Tokita et al. [2] (2016) | c.6233del | p.Pro2078HisfsTer4 | Frameshift | de novo |
| Tokita et al. [2] (2016) | c.3852_3856del | p.Met1284IlefsTer2 | Frameshift | de novo |
| Tokita et al. [2] (2016) | c.286C>T | p.Gln96Ter | Nonsense | de novo |
| Tokita et al. [2] (2016) | c.5753_5756del | p.Val1918GlufsTer87 | Frameshift | de novo |
| Tokita et al. [2] (2016) | c.3073dup | p.Met1025AsnfsTer6 | Frameshift | de novo |
| Tokita et al. [2] (2016) | c.4909A>T; c.5528C>A | p.Thr1637Ser, p.Ser1843Tyr | Missense, Frameshift | de novo |
| Takenouchi et al. [3] (2016) | c.5753_5756del | p.Val1918GlufsTer87 | Frameshift | de novo |
| Kim et al. [4] (2016) | c.5449_5550del | p.Arg1850IlefsTer3 | Frameshift | de novo |
| Kim et al. [4] (2016)1 | c.1881_1882del | p.Val629AlafsTer56 | Frameshift | de novo |
| Kim et al. [4] (2016)2 | c.5753_5756del | p.Val1918GlufsTer87 | Frameshift | de novo |
| Kim et al. [4] (2016) | c.3852_3856del | p.Met1284IlefsTer2 | Frameshift | de novo |
| Kim et al. [4] (2016) | c.5753_5756del | p.Val1918GlufsTer87 | Frameshift | de novo |
| Kim et al. [4] (2016) | c.4999_5013del; c.5031_5032ins | p.Asp1667_Asn1671del; Asp1678LysfsTer9 | Frameshift | de novo |
| Kim et al. [4] (2016) | c.6002_6003ins | p.Arg2002GlnfsTer5 | Frameshift | de novo |
| Kim et al. [4] (2016) | c.4358_4359del | p.Thr1453SerfsTer11 | Frameshift | de novo |
| Kim et al. [4] (2016) | c.4640del | p.His1547LeufsTer76 | Frameshift | de novo |
| Kim et al. [4] (2016) | c.6087del | p.Ser2029ArgfsTer22 | Frameshift | de novo |
| Kim et al. [4] (2016) | c.3597_3598dup | p.Pro1200ArgfsTer17 | Frameshift | de novo |
| Kim et al. [4] (2016) | c.4151_4174del | p.Leu1384_Val1391del | Frameshift | N/A |
| Kim et al. [4] (2016) | c.2365del | p.Ser789AlafsTer8 | Frameshift | de novo |
| Kim et al. [4] (2016) | c.3334C>T | p.Arg1112Ter | Nonsense | de novo |
| Kim et al. [4] (2016) | c.268del | p.Ser90ValfsTer59 | Frameshift | de novo |
| Kim et al. [4] (2016) | c.4055del | p.Pro1352GlnfsTer14 | Frameshift | de novo |
| Kim et al. [4] (2016) | c.4549dup | p.Glu1517GlyfsTer6 | Frameshift | de novo |
| Kim et al. [4] (2016) | c.5753_5756del | p.Val1918GlufsTer87 | Frameshift | de novo |
| Kim et al. [4] (2016) | c.5753_5756del | p.Val1918GlufsTer87 | Frameshift | de novo |
| Kim et al. [4] (2016) | g.34894566_3527867 | Whole gene deletion | de novo | |
| Kim et al. [6] (2019) | c.3334C>T | p.Arg1112Ter | Nonsense | N/A |
| Kim et al. [6] (2019) | c.4678del | p.Glu1560LysfsTer63 | Frameshift | N/A |
| Yang et al. [10] (2019) | c.394C>T | p.Gln132Ter | Nonsense | de novo |
| Quintana Castanedo et al. [11] (2020) | c.1444del | p.Leu482CysTer4 | Frameshift | de novo |
| Yang [12] (2020) | c.5297del | p.Ser1766LeufsTer7 | Frameshift | de novo |
| Slezak [13] (2020) | c.4018del | p.Ala1340GlnfsTer26 | Frameshift | de novo |
| Slezak et al. [13] (2020) | c.4919_4923del | p.Asp1640GlyfsTer7 | Frameshift | de novo |
| Tan et al. [14] (2020) | c.5230del | p.Arg1744ValfsTer29 | Frameshift | de novo |
| Peng et al. [15] (2021) | c.5753_5756del | p. Val1918Glufs*87 | Frameshift | de novo |
| Dingemans et al. [16] (2022) | c.5753_5756del | p.Val1918Glufs*87 | Frameshift | de novo |
| Dingemans et al. [16] (2022) | c.5753_5756del | p.Val1918Glufs*87 | Frameshift | de novo |
| Dingemans et al. [16] (2022) | c.5753_5756del | p.Val1918Glufs*87 | Frameshift | de novo |
| Dingemans et al. [16] (2022) | c.3203C>G | p.Ser1068* | Nonsense | de novo |
| Dingemans et al. [16] (2022) | c.457del | p.Asp153Ilefs*4 | Frameshift | de novo |
| Dingemans et al. [16] (2022) | c.384del | p.Lys128Asnfs*21 | Frameshift | de novo |
| Dingemans et al. [16] (2022) | g.34783136_34975848del | Deletion | de novo | |
| Dingemans et al. [16] (2022) | c.6010del | p.Val2004Trpfs*2 | Frameshift | de novo |
| Dingemans et al. [16] (2022) | c.3711del | p.Ser1238Glnfs*3 | Frameshift | de novo |
| Dingemans et al. [16] (2022) | c.6010del | p.Val2004Trpfs*2 | Frameshift | de novo |
| Dingemans et al. [16] (2022) | c.5753_5756del | p.Val1918Glufs*87 | Frameshift | de novo |
| Dingemans et al. [16] (2022) | c.348_351del | p.Asn116Lysfs*32 | Frameshift | de novo |
| Dingemans et al. [16] (2022) | c.5753_5756del | p.Val1918Glufs*87 | Frameshift | de novo |
| Dingemans et al. [16] (2022) | c.5753_5756del | p.Val1918Glufs*87 | Frameshift | de novo |
| Dingemans et al. [16] (2022) | c.668C>T | p.Ser223Leu | Missense | de novo |
| Dingemans et al. [16] (2022) | c.1881_1882del | p.Val629Alafs*56 | Frameshift | de novo |
| Dingemans et al. [16] (2022) | c.1736C>G | p.Thr579Ser | Missense | de novo |
| Kushary et al. [8] (2021) | c.326_329del | p.Lys109SerfsTer39 | Frameshift | de novo |
| Kushary et al. [8] (2021) | c.3131_3153del | p.Glu1046GlyfsTer2 | Frameshift | de novo |
| Kushary et al. [8] (2021) | c.3408C>A | p.Tyr1136Ter | Nonsense | N/A |
| Kushary et al. [8] (2021) | c.5753_5756del | p.Val1918GlufsTer87 | Frameshift | de novo |
| Kushary et al. [8] (2021) | c.5761C>T | p.Arg1921Ter | Nonsense | N/A |
| Kushary et al. [8] (2021) | c.6461del | p.Asn2154IlefsTer2 | Frameshift | de novo |
| Kushary et al. [8] (2021) | c.4776_4779del | p.Ser1594LeufsTer28 | Frameshift | de novo |
| Kushary et al. [8] (2021) | c.5753_5756del | p.Val1918GlufsTer87 | Frameshift | de novo |
| Kushary et al. [8] (2021) | c.3214C>T | p.Arg1072Cys | Missense | N/A |
| Kushary et al. [8] (2021) | c.2763C>A | p.Tyr921Ter | Nonsense | de novo |
| Kushary et al. [8] (2021) | c.4777_4778del | p.Leu1593IlefsTer11 | Frameshift | de novo |
| Kushary et al. [8] (2021) | c.4448_4452del | p.Val1483GluTer4 | Frameshift | N/A |
| Kushary et al. [8] (2021) | c.2160delC | p.Met721TrpfsTer6 | Frameshift | de novo |
| Kushary et al. [8] (2021) | c.4663delA | p.Thr1555fsTer68 | Frameshift | de novo |
| Kushary et al. [8] (2021) | c.5753_5756del | p.Val1918GlufsTer87 | Frameshift | N/A |
| Yi et al. [17] (2022) | c.5334_5335del | p. Arg1778Serfs*11 | Frameshift | de novo |
| Hudec et al. [20] (2022) | N/A | N/A | N/A | N/A |
| Tang et al. [9] (2023) | c.1845_1870del | p.Gly616Serfs*61 | Frameshift | de novo |
| El-Said et al. [21] (2023) | g.34841458_ 35430729 | 589 kB interstitial homozygous deletion | Deletion | N/A |
| El-Said et al. [21] (2023) | c.27dupT | p.Arg10Ter | Nonsense | de novo |
| Langford et al. [22] (2023) | c.1487del | p.Ala496GlyfsTer2 | Frameshift | de novo |
| Vasquez-Forero et al. [23] (2023) | c.5743C>T | p.Arg1915Ter | Nonsense | de novo |
| Pietrobattista et al. [24] (2023) | c.5751_5754delAGTT | p.Val1918fsTer87 | Frameshift | de novo |
| Our case | c.2145_2146delATinsTCTGGGG | p.Ala717Ter2 | Delins | de novo |
The variant identified in our case represents a novel delins variant, resulting in the replacement of alanine at position 717 with glycine, and premature termination of the protein at two subsequent sites. According to ACMG guidelines, the variant c.2145_2146delATinsTCTGGGG (p.A717Gfs*2) located in exon 3 is predicted to be likely pathogenic as it leads to nonsense-mediated decay (PVS1). Additionally, the variant has a zero frequency in the gnomAD database and has not been detected in our internal database (PM2).
WES is known to be highly valuable for patients presenting with intellectual disability and global developmental delay, particularly when precise diagnostic indicators are absent [26, 27]. In this context, we once again underscore the significance of WES for the early diagnosis of ZTTK syndrome as it can expedite the diagnostic process and facilitate timely and effective management. Given that ZTTK syndrome is a recently described condition, further functional studies are warranted to elucidate the pathogenesis of the disorder and the associations among its manifestations.
In summary, we present a patient with features consistent with ZTTK syndrome, characterized by a novel de novo variant in the SON gene (c.2145_2146delATinsTCTGGGG, p.A717Gfs*2). He exhibited a wide range of behavioral abnormalities, stroke, and recurrent urolithiasis which contribute to the clinical characteristics of the syndrome. It is noteworthy that not all patients with ZTTK syndrome manifest these specific findings. Whole exome sequencing has emerged as highly advantageous for diagnosing cases of intellectual disability and global developmental delay, especially in the absence of precise diagnostic findings.
The manuscript was checked according to CARE Checklist (online suppl. Material 1; for all online suppl. material, see https://doi.org/10.1159/000546621).
Acknowledgments
We are grateful to the patient and his family for participating in this study.
Statement of Ethics
This study protocol was approved by the Institutional Ethics Committee, Inonu University Faculty of Medicine, dated May 20, 2025, and numbered 2025/7805. Written informed consent was obtained from the parents of the patient for publication of the details of his medical case and any accompanying images.
Conflict of Interest Statement
The authors declare no competing interests.
Funding Sources
No financial assistance was received in support of this study.
Author Contributions
K.A. participated in the design of the study, performed physical examination of the patient and whole exome analysis, and wrote the manuscript. M.O. and Z.E. performed the physical examination of the patient. I.T. contributed to the study design and analyzed the exome sequencing data. A.S. provided radiological imaging.
Funding Statement
No financial assistance was received in support of this study.
Data Availability Statement
The data in this article are not publicly available because of concerns regarding patient anonymity. Requests to access the data should be directed to the corresponding author.
Supplementary Material.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data in this article are not publicly available because of concerns regarding patient anonymity. Requests to access the data should be directed to the corresponding author.