Abstract
Background
Intellectual developmental disorder with dysmorphic facial features, seizures, and distal limb anomalies (IDDFSDA, MIM: #617452) is a rare autosomal recessive genetic disorder. There have been < 30 reported cases globally without fundus and retinal lesions.
Methods
Pathogenic gene variants were identified using whole exome trio sequencing (trioWES) and confirmed using Sanger sequencing. The literature on PubMed and Google Scholar was reviewed using the keyword “OTUD6B” to summarize and compare clinical phenotypes and OTUD6B variants in reported cases.
Case presentation
A 6-month-old girl presented with nystagmus and hypothyroidism. On admission, optic disc hypoplasia and retinal abnormalities were detected with a typical phenotype of IDDFSDA. TrioWES was used to identify compound heterozygous novel variants in the OTUD6B gene, namely c.479A > G and c.83-1delG. Significantly, none of the 27 previously reported IDDFSDA cases exhibited ocular developmental abnormalities.
Conclusions
OTUD6B defects correlate with multiple organ abnormalities, possibly including ocular developmental anomalies. Further investigation is required to investigate the association between the newly identified variants c.479A > G or c.83-1delG and ocular development.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12887-025-06272-6.
Keywords: OTUD6B, Intellectual disability, IDDFSDA, Nystagmus, Retinopathy, Developmental delay
Introduction
Intellectual developmental disorder with dysmorphic facial features, seizures, and distal limb abnormalities (IDDFSDA, MIM: #617452) is a rare genetic syndrome characterized by multiple congenital anomalies/dysmorphic features caused by biallelic variants in the OTUD6B gene. It is characterized by varying degrees of developmental delay, intellectual disability, early-onset epilepsy, and dysmorphic facial features, including arched eyebrows, long palpebral fissures, prominent nasal bridge, large ears, a thin upper lip, and a high-arched palate [1]. Other reported features include microcephaly, hypotonia, growth retardation, congenital heart defects, finger and toe abnormalities, and other neurological manifestations, including ataxia or spastic quadriparesis. Some patients exhibit brain imaging abnormalities, including corpus callosum hypoplasia, white matter abnormalities, or cortical atrophy [2–8].
OTUD6B is a ubiquitin-specific deubiquitinating enzyme that is extensively expressed across multiple systems [9–11]. It is essential in various cellular processes, including protein degradation, cell signaling transduction, transcription, protein synthesis, and DNA repair [12]. In previously reported cases [1], truncating mutations in OTUD6B are associated with more severe phenotypes, while missense mutations were associated with relatively milder phenotypes, implying that the extent of functional impairment of OTUD6B may correlate with the severity of the patient's phenotype. Additionally, complete knockout of OTUD6B in mice resulted in embryonic or neonatal lethality [1], suggesting that OTUD6B missense mutations may be associated with the residual function of the altered protein. The genotype–phenotype correlations of OTUD6B variants with IDDFSDA are unclear.
Materials and methods
Ethical statement
This study was approved by the Ethics Committee of Wuhan Children's Hospital (Grant No. 2022R043-E01), and the family of the patient provided written informed consent for access to clinical data and genetic analysis.
Case report
A 6-month-old female patient, born to non-consanguineous healthy parents, presented with nystagmus and hypothyroidism detected during newborn metabolic screening. Ophthalmic evaluation revealed optic disc hypoplasia and retinal abnormalities. During hospitalization in the ophthalmology department, abnormal facial features, developmental delays, and feeding difficulties were observed. Consequently, a multidisciplinary consultation involving the neurology and rehabilitation medicine departments was initiated to perform a comprehensive physical examination and evaluate her neurological development.
The patient is the second child, delivered through the cesarean section at full term, with a birth weight of 2.48 kg, and without complications during delivery. Prenatal anomalies comprised increased fetal nuchal translucency and intrauterine growth restriction. External fixation osteosynthesis was performed for bilateral auricular protrusion on the third day after birth. Magnetic resonance imaging (MRI) of the sacral and coccygeal regions revealed a sacral dimple, which led to the diagnosis of a spinal meningocele at one month. No surgical intervention was performed, and she continued to require diapers at the age of 3 and a half years despite the absence of urinary or bowel problems.
At 5 months, a physical examination of the patient revealed below-average weight (6.0 kg, 3rd–15th percentile), moderate length (65 cm, 10–25th percentile), and microcephaly (head circumference 37 cm, < −3rd percentile; Fig. 1A). Physical features included a broad nasal root, retrognathia, arched eyebrows, large protruding low-set ears, a short neck, a sacral dimple, and overlapping toes. She exhibited delayed responses, difficulty with visual and auditory tracking, horizontal nystagmus of both eyeballs, vocalized when amused, weak head control, limited head lifting ability, inability to grasp objects, sat without support, and supported partial weight while standing, hypotonia of the limbs. Cranial MRI revealed mild irregular enlargement of the bilateral lateral ventricles (Fig. 1B). The ocular MRI did not reveal abnormalities. However, the RetCam examination revealed optic papillary dysplasia and retinopathy (Fig. 1C). The heart and hip joint assessments were normal. Laboratory investigations were within normal ranges, including liver and kidney function, cardiac enzymes, thyroid function,and electrolytes (Fig. 2).
Fig. 1.
Clinical features of the patient. Images of her face, hands, and feet illustrating microcephaly (at 5 months: 37 cm, at 1 year 5 months: 42 cm, at 3 years and a half years: 44 cm, all below −3 standard deviation(SD)), turricephaly, broad nasal root, retrognathia, arched eyebrows, large protruding low-set ears, sacral dimple, abnormal hand creases, and overlapping toes
Fig. 2.
RetCam examination and MRI performed at the age of 6 months. Left revealed bilateral optic disc hypoplasia, with dilated choroidal vessels below the left eye, finer retinal vessels, and narrowed arteries. Uneven retinal pigmentation, with granular changes in some areas. Multiple white circular lesions in the periphery of both eyes, located above the temporal area in the right eye and below the temporal area in the left eye. Right up: Brain MRI revealed mild irregular enlargement of the bilateral lateral ventricles and localized widening of the sulcus. (right down) MRI of the sacral and coccygeal regions performed at the age of 1 month revealed a Tarlov cyst
At 6 months, genetic tests utilizing whole-exome sequencing and copy number variation analysis revealed a genetic mutation in the OTUD6B gene.
She experienced twice episode of febrile seizure At age 13 and 17 months, respectively, and abnormal electroencephalogram (EEG) patterns observed during her sleep in the subsequently test.
The child experienced severe delays in developmental milestones. She achieved head lifting at 5 months and briefly achieved independent sitting at 10 months. Teeth erupted late at approximately 1 year. Before turning 1 year old, she experienced difficulties with swallowing and was prone to choking on milk. After a year of comprehensive hospital-based rehabilitation, marked improvements were observed in her gross motor skills and swallowing ability. At approximately 2 years, she transitioned to solid foods; however, she experienced allergies and recurring eczema. She started walking independently at 2 and a half years, with reduced nystagmus severity. At 3 years and 6 months, she continues to demonstrate severe cognitive and language developmental delay without active language development.
Her newborn metabolic screening showed hypothyroidism, although her parents have misplaced this report.She started levothyroxine sodium tablets that same week. At her last visit, age 3 years 6 months, the dose was down to 12.5 µg daily, with every thyroid check since 3monts age within the normal range.
Genetic tests and variants interpretation
Chigene (Chigene Translational Medical Research Center Co., Ltd., Beijing, China) performed TrioWES and bioinformatics analysis. The assessment of the pathogenicity of candidate variants was informed by the latest discussion of the clinical findings in the the American College of Medical Genetics and Genomics (ACMG) guidelines [13] and the Sequence Variant Interpretation Working Group (SVIWG, https://www.clinicalgenome.org/working-groups/sequence-variant-interpretation/). The analysis of OTUD6B gene variants utilized the reference transcript NM_016023.5.
TrioWES identified OTUD6B compound heterozygous variants, c.479A > G (p.Y160C) and c.83-1del, in the patient, which were confirmed through Sanger sequencing. The ACMG clinical practice guidelines classified the Y160C and c.83-1del variants as likely pathogenic and pathogenic, respectively, with both being previously unreported. The structural conservation analysis of OTUD6B performed using the online ConSerf software (https://consurf.tau.ac.il/) revealed that the Y160 site is significantly evolutionarily conserved (Fig. 3A). Furthermore, we examined adjacent C158, a previously reported residue that affects the function of OTUD6B and is highly conserved. The 3D structural analysis of the OTUD6B Y160C mutant revealed that this mutation creates a thiol group in close spatial proximity to C158, implying that the two cysteine residues may form a disulfide bond (Fig. 3B). An AI-powered splicing prediction method (provided by the Rare Disease Data Center, RDDC, https://rddc.tsinghua-gd.org) was utilized to validate the OTUD6B c.83-1del variant. The analysis revealed that the variant induces three distinct splicing patterns, leading to premature mRNA transcription termination (Fig. 3C).
Fig. 3.
Structural conservation analysis of the OTUD6B Y160C variant and splicing prediction of OTUD6B c.83-1del variant. A The two arrows indicate the Y160 and previously reported C158 sites. B The Y160C variant allows it to potentially form a disulfide bond with the spatially proximal C158. C OTUD6B c.83-1del variant leads to three types of slicing variation, resulting in premature mRNA transcription termination. The conservation analysis of OTUD6B amino acid residues was performed using the ConSurf online tool (https://consurf.tau.ac.il/), and the 3D protein structure images were generated using PyMol software (version 2.5.8). The OTUD6B protein model used was AlphaFold AF-Q8N6M0-F1-model_v4. Splicing prediction used an AI-powered method provided by the RDDC of the Guangzhou Rare Disease Gene Therapy Alliance, China
Discussion
Intellectual disability, facial dysmorphism, epilepsy, and abnormalities in distal limb development are the four hallmark features for the diagnosis of IDDFSDA, MIM: #617452. Although these phenotypes are commonly observed in neurodevelopmental disorders, their specific combination uniquely defines the syndrome [1–4, 6, 7, 14]. The initial Chinese patient with IDDFSDA identified in this study exhibited the characteristic features of the IDDFSDA syndrome, meeting the diagnostic criteria for the condition. However, the ocular abnormalities and hypothyroidism observed in our case have not been reported in previous cases. There is only one report of a patient with IDDFSDA who presented with nystagmus [3] associated with ocular abnormalities, possibly indicating that eye abnormalities may be a characteristic feature of IDDFSDA.
DUB gene mutations are implicated in various neurological disorders [12]. Table 1 presents the clinical characteristics of 27 patients, with over 80% of them presenting with seizures or seizure-like episodes. However, even among individuals possessing identical genetic variants, there was significant variability in the types and severity of seizures [14]. Two patients in the entire population did not exhibit this symptom. In this case, the patient experienced two episodes of febrile seizures before 18 months of age, although she was not formally diagnosed with epilepsy. Because of the clinical presentation of the patient, EEG monitoring, and genetic analysis findings, the pediatric neurosurgeon considered a high likelihood of developing epilepsy in the future and thus prescribed levetiracetam (1 mL, twice daily), which ameliorated the seizures. Microcephaly is a characteristic feature of IDDFSDA, observed in 81% (23/28) of patients. Facial dysmorphism and distal limb abnormalities are distinctive and identifiable features of this syndrome. The facial dysmorphic features manifest as abnormal development of facial structures: broad forehead, long and narrow face, bilateral ptosis, deep-set orbits, down-slanting palpebral fissures, prominent and protruding low-set ears, broad nasal root, elongated nose, extended philtrum, high-arched palate, thin upper lip, arched eyebrows, and sparse eyebrows. These features are diagnostic indicators for clinicians, and they were present in our patient, including distinctive facies and overlapping toes.
Table 1.
Clinical findings of previously reported OTUD6B-related IDDFSDA cases with our case
| Clinical features | Specific features | Frequency reported in the literature | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Our case | Santiago-Sim et al.(n = 12) | Straneiro et al. (n = 1) | Sánchez-Soler et al. (n = 1) | Alkuraya et al. (n = 1) | Romero-Ibarguengoitia et al. (n = 1) | Abdel-Salam et al. (n = 5) | Phetthong et al. (n = 1) | Börklü et al. (n = 1) | Cingöz S et al. (n = 1) | Gangaram et al. (n = 3) | Total (%) (n = 28) | ||
| Age (at reporting) | 6 months | 3.9–20 years | 6 years | 3 months | 10 months | 10 years | 6–24 years | 3.5 years | 4 years | 17 years | 4.5–9 years | ||
| Gender | F | M:8/12; F:4/12 | F | F | F | M | M:3/5; F:2/5 | F | M | M | F:3/3 |
M:14/28(50) F:14/28(50) |
|
| IDDFSD, a phenotypic | |||||||||||||
| Intellectual disability | (+) | 12/12 | 1/1 | 1/1 | 1/1 | 1/1 | 5/5 | 1/1 | 1/1 | 1/1 | 3/3 | 28/28(100) | |
| Dysmorphic facies | |||||||||||||
| Head/neck | wide forehead, narrow long face | + | 10/12 | 1/1 | NA | 1/1 | 1/1 | 5/5 | 1/1 | 0/1 | 1/1 | 3/3 | 26/27 |
| Eyes | bilateral ptosis, deep-set eyes, down-slanting palpebral fissures | + | 9/12 | 1/1 | 1/1 | 1/1 | 1/1 | 5/5 | 0/1 | 1/1 | 1/1 | 3/3 | 24/28 |
| Ears |
large protruding, low-set ears |
+ | 10/12 | 1/1 | 1/1 | 0/1 | 1/1 | 5/5 | 1/1 | 1/1 | 1/1 | 3/3 | 25/28 |
| Noses | broad nasal root, long nose, long philtrum | + | 6/12 | 1/1 | 1/1 | 1/1 | 1/1 | 5/5 | 1/1 | 1/1 | 1/1 | 3/3 | 22/28 |
| Mouth |
high-arched, palate thin upper lip |
+ | 10/12 | 1/1 | 1/1 | 1/1 | 1/1 | 5/5 | 1/1 | 1/1 | 1/1 | 3/3 | 26/28 |
| Eyebrow |
arched eyebrows Sparse eyebrows |
+ | 7/12 | 1/1 | 1/1 | 1/1 | 1/1 | 5/5 | 1/1 | 0/1 | 1/1 | 3/3 | 22/28 |
| Microcephaly | + | 9/12 | 1/1 | 1/1 | 1/1 | 1/1 | 4/4 | 0/1 | 1/1 | 1/1 | 2/3 | 23/28 | |
| Seizures | - | 12/12 | 1/1 | 1/1 | 1/1 | 1/1 | 3/4 | 1/1 | 0/1 | 1/1 | 3/3 | 25/28 | |
| Distal limb anomalies |
broad limbs, interphalangeal joints hyperextensibility, clubfeet, overlapping toe, arachnodactyly, hyperextensibility elbows |
+ | 11/12 | 1/1 | 1/1 | 1/1 | 1/1 | 5/5 | 1/1 | 1/1 | 1/1 | 2/3 | 26/28 |
| Nervous system | |||||||||||||
| Cranial MRI | + | 6/12 | 0/1 | 1/1 | 0/1 | NA | 4/4 | NA | NA | 1/1 | 2/3 | 13/24 | |
| Cerebella signs | - | 0/12 | 0/1 | 0/1 | 0/1 | NA | 1/4 | NA | NA | 0/1 | 0/3 | 1/24 | |
| EEG abnormal | + | NA | NA | 0/1 | 0/1 | 1/1 | 2/3 | NA | NA | 1/1 | NA | 5/8 | |
| Motor delay | + | 9/12 | 1/1 | NA | 1/1 | 1/1 | 5/5 | 1/1 | 1/1 | 1/1 | 3/3 | 24/27 | |
| Speech delay | + | 9/12 | 1/1 | 1/1 | 1/1 | 1/1 | 5/5 | 1/1 | 1/1 | 1/1 | 3/3 | 25/28 | |
| Musculoskeletal system | |||||||||||||
| Spasticity | - | 2/12 | 0/1 | 0/1 | 1/1 | 0/1 | NA | 0/1 | NA | 1/1 | 0/3 | 4/22 | |
| Hypotonia | + | 9/12 | 1/1 | 1/1 | NA | 1/1 | NA | NA | NA | 1/1 | 2/2 | 16/18 | |
| Sacral dimple | + | 2/12 | 0/1 | 0/1 | NA | 1/1 | 1/5 | NA? | 0/1 | NA | 3/3 | 8/25 | |
| Scoliosis | - | 5/12 | 0/1 | 0/1 | 0/1 | 1/1 | NA | NA | 0/1 | 1/1 | 1/3 | 8/22 | |
| Delayed growth | |||||||||||||
| Short stature(< −2 SD) | + | 8/12 | 0/1 | 1/1 | 1/1 | 1/1 | 1/5 | 0/1 | 0/1 | 1/1 | 2/3 | 16/28 | |
| Poor weight gain(< −2 SD) | + | 6/12 | 0/1 | 1/1 | 1/1 | 1/1 | 0/5 | 0/1 | 1/1 | 1/1 | 2/3 | 14/28 | |
| Delayed primary teeth eruption | + | NA | NA | 1/1 | NA | NA | NA | NA | NA | NA | 3/3 | 5/5 | |
| Cardiovascular system | congenital heart disease | - | 4/9 | 1/1 | 0/1 | 1/1 | 1/1 | 1/3 | 1/1 | 1/1 | 1/1 | 0/3 | 11/25 |
| Gastrointestinal system |
Feeding/swallowing difficulty |
+ | 9/12 | 1/1 | 1/1 | 1/1 | 1/1 | NA | 0/1 | NA | 1/1 | 1/3 | 16/22 |
| Renal abnormal | - | 0/12 | 0/1 | 1/1 | 1/1 | NA | 0/3 | 0/1 | 1/1 | 1/1 | 0/3 | 4/25 | |
| Reproductive systems | cryptorchidism | - | 4/12 | 0/1 | 0/1 | 0/1 | NA | 2/3 | 0/1 | NA | 1/1 | 0/3 | 7/24 |
| Endocrine systems | hypothyroidism | + | 2/12 | NA | NA | NA | 1/1 | 0/5 | 0/1 | NA | NA | 0/3 | 4/23 |
| Skin/subcutaneous tissue | amenorrhea | + | NA | NA | 0/1 | 0/1 | NA | NA | NA | NA | NA | 3/3 | 4/6 |
| Ophthalmologic abnormalities | nystagmus, optic papillary dysplasia, fundus lesions, esotropia | + | NA | 1/1a | 1/1b | 0/1 | 0/1 | 2/5c | 0/1 | NA | NA | NA | 6/11 |
F Female, M Male, NA not available
aDuane syndrome (restricted horizontal eye movement)
bStrabismus
cRetinal degeneration due to a coincidental disorder caused by homozygous RP1L1 mutation
Five patients (18%, 5/28), including the patient in this case, experienced delayed tooth eruption associated with skeletal abnormalities; however, our patient did not present with more common musculoskeleta phenotypes, kyphosis (8/25) and scoliosis (8/22), and hypotonia (16/18) (Table 1). Furthermore, in our patient, no congenital heart defects, gastrointestinal abnormalities, or reproductive and urinary system anomalies were identified. However, phenotypes that are rare or have never been reported include delayed primary tooth eruption, recurrent infantile eczema, hypoproteinemia, hypothyroidism, dysphagia, and congenital eye abnormalities, indicating a high degree of phenotypic heterogeneity in the multisystemic manifestations of IDDFSDA.
Patchy retinal pigmentation indicates retinal vascular attenuation, which was previously reported in two cases of retinal degeneration within the same family by Abdel-Salam et al. [2], although they were excluded from having the OTUD6B gene mutations. These findings indicate that ocular involvement may be an overlooked phenotypic feature in patients with IDDFSDA.
The OTUD6B Y160C variant has not been previously reported in Single Nucleotide Polymorphism(SNP) databases, making it a scarce variant that may have a pathogenic effect by impacting the function of C158. Previous studies reported that the C158S mutation inhibits the protein from cleaving the Ub-Met-β-gal substrate, thereby disrupting the deubiquitination function of OTUD6B [15]. Our conservation analysis of the OTUD6B amino acid sequence revealed that C158 is a highly conserved residue without adjacent cysteine residues (Fig. 3A), while the adjacent mutation Y160C may potentially form a disulfide bond with it (Fig. 3B). The OTUD6B c.83-1del variant induces three types of slicing variation, culminating in premature termination of mRNA transcription (Fig. 3C). Protein secondary structures, including alpha helices, are predominantly formed through hydrogen bonding and other non-covalent interactions; however, disulfide bonds can indirectly affect the formation and maintenance of these secondary structures by restricting chain flexibility and increasing structural stability, thereby affecting proper protein folding. Thiols are closely associated with the functionality of numerous enzymes; for instance, specific heavy metal ions (mercury) can bind to enzyme thiols, inhibiting their activity. Furthermore, the typical functioning C158 of OTUD6B can facilitate its biochemical actions by establishing disulfide bonds with other ligands, and the disulfide bond formed with C160 may exert an antagonistic effect. Unlike the truncating mutations associated with more severe phenotypes [1], including the newly identified c.83-1delG in this study, the missense variant Y160C, associated with milder phenotypes, may pertain to functional alteration rather than complete loss of function. Identifying additional cases with the Y160C variant would clarify whether this variant is associated with specific phenotypic characteristics, including eye abnormalities and hypothyroidism.
In conclusion, our study identified the rare variants OTUD6B Y160C and c.83-1del in the first Chinese patient with IDDFSDA, providing additional clinical insight into the understanding of IDDFSDA and enriching the mutation spectrum of the OTUD6B gene. Our identification of the visual system abnormalities in this syndrome highlights the clinical phenotypic heterogeneity of the condition, providing a crucial reference for the future clinical diagnosis and differentiation of the disease.
Supplementary Information
Acknowledgements
We are grateful to the patient and parents who supported our study.
Authors’ contributions
Jing Chen, Dan Gao and Juan Hu wrote the main manuscript text. Ke Xu performed the molecular analysis and interpreted the genetic data. Weiyue Gu prepared Figs. 1 and 2. Hongmin Zhu and Jingjing Li conceived and designed the experiments, prepared figures and table, authored drafts of the article. All authors reviewed the manuscript.
Funding
This research was supported by the “Hubei Provincial Science and Technology Plan Project for the Clinical Research Center of Neurodevelopmental Disorders in Children (No. 2022DCC020)” and “A multicenter, prospective, randomized controlled study of the medium-chain triglyceride diet for the treatment of global developmental delay in children (No. 2022FE005)”.
Data availability
All data generated or analyzed during this study are included in this published article. The original contributions presented in this study are publicly available. The OTUD6B variants c.479 (exon 4) A > G and c.83–1 (IVS1) delG were submitted to the ClinVar database. The ID numbers are SCV005326498 and SCV005326499. The URL links: https://www.ncbi.nlm.nih.gov/clinvar/variation/3341106/?oq=SCV005326498&m=NM_016023.5(OTUD6B):c.479A%3EG%20(p.Tyr160Cys), https://www.ncbi.nlm.nih.gov/clinvar/variation/3341105/?oq=SCV005326499&m=NM_016023.5(OTUD6B):c.83-1del.
Declarations
Ethics approval and consent to participate
The patient was admitted to the rehabilitation department of Wuhan Children’s Hospital in June 2021. All procedures performed in studies involving human participants were conformed to the ethical guidelines of the 1975 Declaration of Helsinki and approved by the Ethical Committee of Wuhan Children’s Hospital (Ethical approval number: 2022R043-E01). Written informed consent for genetic analysis was obtained from the parents of the affected individual.
Consent for publication
Written informed consent was obtained from the patient’s parents for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the editor of this journal.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jing Chen, Dan Gao and Juan Hu contributed equally to this work.
Contributor Information
Jingjing Li, Email: 154899649@qq.com.
Hongmin Zhu, Email: zhuyan44@163.com.
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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
All data generated or analyzed during this study are included in this published article. The original contributions presented in this study are publicly available. The OTUD6B variants c.479 (exon 4) A > G and c.83–1 (IVS1) delG were submitted to the ClinVar database. The ID numbers are SCV005326498 and SCV005326499. The URL links: https://www.ncbi.nlm.nih.gov/clinvar/variation/3341106/?oq=SCV005326498&m=NM_016023.5(OTUD6B):c.479A%3EG%20(p.Tyr160Cys), https://www.ncbi.nlm.nih.gov/clinvar/variation/3341105/?oq=SCV005326499&m=NM_016023.5(OTUD6B):c.83-1del.