Clinical characteristics.

TBCK-related neurodevelopmental disorder (TBCK-NDD) is typically a progressive condition in which individuals have significant developmental and respiratory issues. A majority of affected individuals do not achieve independent ambulation or spoken language. Most affected individuals also have congenital and severe hypotonia, which can also lead to feeding issues and dysphagia, with many affected individuals requiring gastrostomy tube placement. Neuromuscular weakness usually affects the distal muscles first, leading to distal muscle wasting, and then the proximal muscles become involved. Electrophysiologic studies suggest that weakness is secondary to a motor neuronopathy. Respiratory issues are also progressive, with most affected individuals requiring noninvasive nocturnal respiratory support by age five years and about 75% of teenagers requiring a tracheostomy. Seizures are also common, and brain MRI imaging may show white matter lesions and progressive cortical atrophy over time. Most affected individuals exhibit some degree of developmental regression and/or neurologic decompensation in the setting of illness, which often raises clinical concerns for mitochondrial disorders. Other features include vision issues (including optic atrophy), the development of contractures and neuromuscular scoliosis, coarsening of facial features over time, recurrent nephrolithiasis and/or urinary tract infections, dyslipidemia without clear adverse cardiovascular events, and the development of left ventricular hypertrophy.

Diagnosis/testing.

The diagnosis of TBCK-NDD is established in a proband with suggestive findings and biallelic pathogenic variants in TBCK identified by molecular genetic testing.

Management.

Treatment of manifestations: Gastrostomy tube placement may be required for ongoing feeding issues and/or dysphagia. Nocturnal ventilatory support and/or tracheostomy may be required for those who have apnea and/or progressive neuromuscular weakness. Standard treatment for developmental delay / intellectual disability / neurobehavioral issues, epilepsy, neuromuscular weakness, spasticity/contractures, growth deficiency, bowel dysfunction, pancreatitis, osteopenia / frequent fractures, eye/vision issues, left ventricular hypertrophy, recurrent urinary tract infections, nephrolithiasis, and neurogenic bladder. No treatment is typically necessary for macroglossia. It remains unclear if treatment of dyslipidemia has a clinically meaningful impact.

Surveillance: At each visit: measure growth parameters and evaluate nutritional status and safety of oral intake; monitor for constipation and signs/symptoms of pancreatitis; monitor for signs/symptoms of chronic respiratory insufficiency, nocturnal hypoventilation, and apnea; assess for new manifestations, such as seizures, changes in tone, and weakness; monitor those with seizures as clinically indicated; assess for developmental progress and educational needs; assess for neurobehavioral concerns; and assess for progressive contractures and bony fractures. Annually or as clinically indicated: ophthalmology evaluation. Every one to two years: complete lipid panel; echocardiogram to assess for left ventricular hypertrophy (if symptomatic; or starting in adolescence). Every two to three years: DXA scan to evaluate for osteopenia. Based on clinical concern: sleep study; evaluation for urinary tract infections, neurogenic bladder, and nephrolithiasis.

Agents/circumstances to avoid: Some affected individuals have been reported to have adverse effects to bisphosphonate infusions for management of osteoporosis. The frequency and mechanism of this observation in the TBCK-NDD population remain unclear, so close monitoring is advised if bisphosphonates are clinically indicated.

Genetic counseling.

TBCK-NDD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TBCK pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the TBCK pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

TBCK-NDD should be considered in probands with the following clinical, laboratory, and brain MRI findings and family history.

Clinical findings

• Severe-to-profound developmental delay (DD) and/or intellectual disability (ID)
• Severe hypotonia, typically congenital
• Infantile feeding difficulties
• Neuromuscular weakness, often progressive, with progressive spasticity and distal muscle wasting
• Respiratory insufficiency or failure (not always congenital but often progressive due to neuromuscular weakness)
• Epilepsy
• Short stature, specifically brachymelia
• Ophthalmologic involvement, including nystagmus and cortical visual impairment
• Coarse facial features with further dysmorphic features (See Clinical Description, Facial features.)

Supportive laboratory findings. Dyslipidemia, including elevated cholesterol (total and low-density lipoprotein) ± triglycerides, frequently identified in childhood

Brain MRI findings. Brain imaging findings that may be progressive, typically with minimal abnormalities at birth. Over time the following have been observed:

• White matter changes, including periventricular lesions
• Cerebellar hypoplasia
• Diffuse brain atrophy
• Thin corpus callosum

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of TBCK-NDD is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in TBCK identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic TBCK variants of uncertain significance (or of one known TBCK pathogenic variant and one TBCK variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with exome sequencing / genome sequencing [Manickam et al 2021, van der Sanden et al 2023]. Other options include use of chromosomal microarray or a multigene panel. Note: Single-gene testing (sequence analysis of TBCK, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• A multigene panel that includes TBCK and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. Due to a recurrent exon 23 deletion that can be missed on an exome-based platform, targeted deletion/duplication analysis and/or genome sequencing may be preferable if a multigene panel is nondiagnostic [Dai et al 2022] (see Molecular Genetics). (2) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used, genome sequencing is also possible. It should be noted that a common deletion of exon 23 in TBCK may be missed on an exome-based platform, which may also be used for multigene panels [Dai et al 2022]. Deletions encompassing this exon may be detectable using next-generation sequencing gene panels, deletion/duplication testing, or whole-genome sequencing (see Molecular Genetics).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

To date, at least 117 individuals have been identified [E Durham, personal observation] and 73 individuals have been reported in the literature with biallelic pathogenic variants in TBCK [Bhoj et al 2016, Chong et al 2016, Guerreiro et al 2016, Mandel et al 2017, Beck-Wödl et al 2018, Hartley et al 2018, Ortiz-González et al 2018, Sumathipala et al 2019, Zapata-Aldana et al 2019, Liu et al 2020, Saredi et al 2020, Tsang et al 2020, Murdock et al 2021, Dai et al 2022, Moreira et al 2022, Tan et al 2022, De Luca-Ramirez et al 2023, Sabanathan et al 2023]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay (DD) and intellectual disability (ID). Gross and fine motor delays are often severe, with a majority of affected individuals unable to ambulate independently during their lifetime. Speech delay can vary, with some affected individuals able to use spoken language, although the majority of affected individuals are nonverbal. Anecdotally, communication devices, including eye gaze devices, have been very helpful for some affected individuals to facilitate communication.

Neurologic features

• Hypotonia is typically congenital and severe and may lead to feeding difficulties (see Gastrointestinal/feeding issues in this section). Over time, central hypotonia with peripheral spasticity develops.
• Neuromuscular weakness is often progressive affecting first distal and then proximal muscles, often leading to progressive spasticity and distal muscle wasting. The creatine kinase level is typically normal and electrophysiologic studies (electromyography / nerve conduction studies) suggest that weakness is secondary to a motor neuronopathy [Ortiz-González et al 2018].
• Epilepsy. The majority (>75%) of affected individuals experience seizures.
  • Seizures provoked by fever during infancy are common.
  • Later in childhood, seizures progress most commonly to symptomatic multifocal epilepsy, although epilepsy syndromes including infantile spasms and Lennox-Gastaut syndrome have been reported. Published data is insufficient to determine frequency of these less common epilepsy syndromes in affected individuals.
  • Some affected individuals experience progression to medication-refractory epilepsy with mixed focal and generalized features in adolescence/adulthood [X Ortiz-Gonzalez, personal observation].
• Neuroimaging. Pathologic brain MRI findings are commonly reported and include general atrophy, abnormal white matter including hyperintensities, ventricular abnormalities, and abnormal corpus collosum. MRI findings such as white matter lesions and cortical atrophy often become more prominent with age. Some affected individuals, including those homozygous for the pathogenic TBCK Boricua founder variant, show evidence of progressive atrophy on serial imaging [Ortiz-González et al 2018] (see Genotype-Phenotype Correlations).

Neurobehavioral/psychiatric manifestations. There is a paucity of data reported on neuropsychiatric manifestations in affected individuals. As most affected individuals are nonverbal and globally delayed, accurate assessment of neuropsychiatric comorbidities remains very limited. Still, autism spectrum disorder (ASD), bipolar disorder, inappropriate behavior, and self-harm have been reported [Bhoj et al 2016, Hartley et al 2018, Zapata-Aldana et al 2019, Lee et al 2020].

Growth. Postnatal growth deficiency is frequent, with most affected individuals exhibiting short stature and brachymelia [Ortiz-González et al 2018, Dai et al 2022].

• Reports of head size have been variable in the literature, with some affected individuals demonstrating microcephaly and some macrocephaly, but most are normocephalic.
• Head asymmetry, brachycephaly, plagiocephaly, and turricephaly have all been reported [Bhoj et al 2016, Chong et al 2016, Guerreiro et al 2016, Mandel et al 2017, Zapata-Aldana et al 2019, Lee et al 2020, Dai et al 2022, De Luca-Ramirez et al 2023, Sabanathan et al 2023].

Gastrointestinal issues/feeding. Infant feeding difficulties are common, including dysphagia in childhood, with many affected individuals requiring gastrostomy tubes for feeding due to risk of aspiration (see Management). gastroesophageal reflux disease, constipation, and abdominal distention have also been reported [Chong et al 2016, Mandel et al 2017, Zapata-Aldana et al 2019, Dai et al 2022, Sabanathan et al 2023]. Pancreatitis has been rarely observed, although it remains unclear if this may be due to any particular precipitating factors, such as elevated triglyceride levels.

Respiratory abnormalities. Affected individuals typically develop chronic respiratory insufficiency and hypoventilation due to progressive neuromuscular weakness, often requiring a consistent pulmonary clearance ("toilet") regimen and increasing ventilatory support with age [Bhoj et al 2016, Chong et al 2016, Ortiz-González et al 2018, Zapata-Aldana et al 2019, Dai et al 2022, Sabanathan et al 2023]. Apnea has also been described in a small subset of affected individuals [Dai et al 2022].

• By age five years, noninvasive nocturnal respiratory support is often required.
• About 75% of affected teenagers require tracheotomy support.

Ophthalmologic involvement. Overall, around 75% of individuals with TBCK-NDD report vision-related symptoms [Durham et al 2023]. Features may include ptosis, nystagmus, strabismus, and/or optic atrophy.

Musculoskeletal features. Along with progressive spasticity, contractures are common but are not typically congenital. An increased risk of osteopenia and bone fractures has been reported [Ortiz-González et al 2018]. Neuromuscular scoliosis has also been observed.

Facial features. Dysmorphic features may include bitemporal narrowing, arched eyebrows, a tented vermilion of the upper lip, and macroglossia. Coarsening of the facial features may develop over time.

Genitourinary abnormalities. Recurrent nephrolithiasis, recurrent urinary tract infections (UTIs), neurogenic bladder, and nephrocalcinosis have all been reported [Bhoj et al 2016, Chong et al 2016, Ortiz-González et al 2018, Dai et al 2022]. Kidney stones can lead to recurrent obstructions or UTIs, often presenting in adolescence [Ortiz-González et al 2018]. Structural renal anomalies have not been reported.

Cardiovascular/dyslipidemia. Dyslipidemia is common but without clear adverse cardiovascular events.

• Left ventricular hypertrophy may develop in late adolescence / early adulthood.
• There are fewer than ten reports of various congenital cardiac anomalies in affected individuals; it is unclear if structural heart defects are a rare finding in affected individuals or if this represents a rare co-occurrence of two unrelated diagnoses [Mastromoro et al 2025].

Prognosis. Although not reported in the literature, the oldest known affected individual is age 34 years [E Durham, personal observation]. The authors' clinical experience is that complications of respiratory infections, status epilepticus, or recurrent episodes of urosepsis are often associated with end of life [X Ortiz-Gonzalez, personal observation].

Genotype-Phenotype Correlations

The TBCK pathogenic variant c.376C>T (p.Arg126Ter) has been proposed as a founder variant in individuals of Puerto Rican ancestry. Affected individuals who have biallelic pathogenic p.Arg126Ter variants tend to have a more severe progressive and neurodegenerative course, including chronic respiratory failure and tracheostomy dependency [Ortiz-González et al 2018].

Prevalence

Prevalence may be as high as 1:1,000,000 worldwide but is about four times higher in Admixed American populations, including the Boricua c.376C>T (p.Arg126Ter) pathogenic variant common in Puerto Rico (see Rare Genomes Project - Disease Prevalence Study).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TBCK-NDD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for TBCK-NDD. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Anecdotally, some affected individuals have had adverse effects to bisphosphonate infusions for management of osteoporosis. The frequency and mechanism of this observation in the TBCK-NDD population remain unclear, so close monitoring is advised if bisphosphonates are clinically indicated [X Ortiz-Gonzalez, personal observation].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

TBCK-related neurodevelopmental disorder (TBCK-NDD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a TBCK pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a TBCK pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a TBCK pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with TBCK-NDD are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a TBCK pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the TBCK pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. A founder variant has been identified in individuals of Puerto Rican ancestry (see Table 7).

Prenatal Testing and Preimplantation Genetic Testing

Once the TBCK pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TBCK encodes TBC domain-containing kinase-like protein (TBCK) [Chong et al 2016]. The physiologic function of TBCK is incompletely understood. Knockdown of this protein is associated with down-regulation of mTORC1 signaling in HEK293 cells [Liu et al 2013]. Fibroblasts derived from individuals with TBCK-NDD show evidence of aberrant autophagy and mitochondrial respiratory defects, which are hypothesized to be secondary to impaired mitochondrial quality control as a result of lysosomal dysfunction [Ortiz-González et al 2018, Tintos-Hernández et al 2021]. Neuropathologic data also support a significant role for autophagic-lysosomal dysfunction in the pathophysiology of TBCK-related neurodevelopmental disorder (TBCK-NDD), revealing the accumulation of intraneuronal lipofuscin storage material [Beck-Wödl et al 2018].

TBCK was recently found to be a component of a novel mRNA transport complex called the five-subunit endosomal Rab5 and RNA/ribosome intermediary (FERRY) complex. Intriguingly, of the five proteins proposed to form the FERRY complex (TBCK, PP1R21, C12orf4, CRYZL1, and GATD1) [Schuhmacher et al 2023], three of them are associated with severe, pediatric-onset neurologic disorders. Therefore, ongoing research is exploring the possible role of mRNA trafficking defects in the pathogenesis of TBCK-NDD [X Ortiz-Gonzalez, unpublished data].

Mechanism of disease causation. Loss of function

TBCK-specific laboratory technical considerations. A recurrent single exon 23 deletion has been identified that could be missed on typical whole-exome sequencing analysis [Burdick et al 2020]. Methods that allow the detection of this deletion include deletion/duplication analysis methods (e.g., chromosomal SNP microarray, multiplex ligation-dependent protein amplification [MLPA]) or whole-genome sequencing. In one study, transcriptome sequencing detected this deletion [Murdock et al 2021].

Author Notes

Children's Hospital of Philadelphia TBCK-related neurodevelopmental disorder web page

Acknowledgments

We are thankful to the TBCK foundation for their ongoing support and advocacy.

Revision History

• 12 June 2025 (ma) Review posted live
• 31 October 2024 (xog) Original submission

Literature Cited

• Beck-Wödl S, Harzer K, Sturm M, Buchert R, Riess O, Mennel HD, Latta E, Pagenstecher A, Keber U. Homozygous TBC1 domain-containing kinase (TBCK) mutation causes a novel lysosomal storage disease - a new type of neuronal ceroid lipofuscinosis (CLN15)? Acta Neuropathol Commun. 2018;6:145. [PMC free article: PMC6307319] [PubMed: 30591081]
• Bhoj EJ, Li D, Harr M, Edvardson S, Elpeleg O, Chisholm E, Juusola J, Douglas G, Guillen Sacoto MJ, Siquier-Pernet K, Saadi A, Bole-Feysot C, Nitschke P, Narravula A, Walke M, Horner MB, Day-Salvatore DL, Jayakar P, Vergano SA, Tarnopolsky MA, Hegde M, Colleaux L, Crino P, Hakonarson H. Mutations in TBCK, encoding TBC1-domain-containing kinase, lead to a recognizable syndrome of intellectual disability and hypotonia. Am J Hum Genet. 2016;98:782-8. [PMC free article: PMC4833465] [PubMed: 27040691]
• Burdick KJ, Cogan JD, Rives LC, Robertson AK, Koziura ME, Brokamp E, Duncan L, Hannig V, Pfotenhauer J, Vanzo R, Paul MS, Bican A, Morgan T, Duis J, Newman JH, Hamid R, Phillips JA, 3rd, Undiagnosed Diseases N. Limitations of exome sequencing in detecting rare and undiagnosed diseases. Am J Med Genet A. 2020;182:1400-6. [PMC free article: PMC8057342] [PubMed: 32190976]
• Chong JX, Caputo V, Phelps IG, Stella L, Worgan L, Dempsey JC, Nguyen A, Leuzzi V, Webster R, Pizzuti A, Marvin CT, Ishak GE, Ardern-Holmes S, Richmond Z, University of Washington Center for Mendelian G, Bamshad MJ, Ortiz-Gonzalez XR, Tartaglia M, Chopra M, Doherty D. Recessive inactivating mutations in TBCK, encoding a Rab GTPase-activating protein, cause severe infantile syndromic encephalopathy. Am J Hum Genet. 2016;98:772-81. [PMC free article: PMC4833196] [PubMed: 27040692]
• Dai H, Zhu W, Yuan B, Walley N, Schoch K, Jiang Y-H, Phillips JA, Jones MS, Liu P, Murdock DR, Burrage LC, Lee B, Rosenfeld JA, Xiao R, Network UD. A recurrent single-exon deletion in TBCK might be under-recognized in patients with infantile hypotonia and psychomotor delay. Hum Mutat. 2022;43:1816-23. [PMC free article: PMC9772143] [PubMed: 36317458]
• De Luca-Ramirez J, Rosado Fernández S, Torres OA. Raising awareness of TBC1 domain-containing kinase (TBCK) epileptic encephalopathy among Puerto Rican children. Ann Child Neurol Soc. 2023;1:168-71.
• Durham EL, Angireddy R, Black A, Melendez-Perez A, Smith S, Gonzalez EM, Navarro KG, Díaz A, Bhoj EJK, Katsura KA. TBCK syndrome: a rare multi-organ neurodegenerative disease. Trends Mol Med. 2023;29:783-5. [PMC free article: PMC10868401] [PubMed: 37455236]
• Guerreiro RJ, Brown R, Dian D, de Goede C, Bras J, Mole SE. Mutation of TBCK causes a rare recessive developmental disorder. Neurol Genet. 2016;2:e76. [PMC free article: PMC4881620] [PubMed: 27275012]
• Hartley T, Wagner JD, Warman-Chardon J, Tétreault M, Brady L, Baker S, Tarnopolsky M, Bourque PR, Parboosingh JS, Smith C, McInnes B, Innes AM, Bernier F, Curry CJ, Yoon G, Horvath GA, Bareke E, Gillespie M, Consortium FC, Consortium CRC, Majewski J, Bulman DE, Dyment DA, Boycott KM. Whole-exome sequencing is a valuable diagnostic tool for inherited peripheral neuropathies: outcomes from a cohort of 50 families. Clin Genet. 2018;93:301-9. [PubMed: 28708278]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
• Landrum MJ, Chitipiralla S, Kaur K, Brown G, Chen C, Hart J, Hoffman D, Jang W, Liu C, Maddipatla Z, Maiti R, Mitchell J, Rezaie T, Riley G, Song G, Yang J, Ziyabari L, Russette A, Kattman BL. ClinVar: updates to support classifications of both germline and somatic variants. Nucleic Acids Res. 2025;53:D1313-D1321. [PMC free article: PMC11701624] [PubMed: 39578691]
• Lee H, Huang AY, Wang LK, Yoon AJ, Renteria G, Eskin A, Signer RH, Dorrani N, Nieves-Rodriguez S, Wan J, Douine ED, Woods JD, Dell'Angelica EC, Fogel BL, Martin MG, Butte MJ, Parker NH, Wang RT, Shieh PB, Wong DA, Gallant N, Singh KE, Tavyev Asher YJ, Sinsheimer JS, Krakow D, Loo SK, Allard P, Papp JC, Palmer CGS, Martinez-Agosto JA, Nelson SF; Undiagnosed Diseases Network. Diagnostic utility of transcriptome sequencing for rare Mendelian diseases. Genet Med. 2020;22:490-9. [PMC free article: PMC7405636] [PubMed: 31607746]
• Liu D, Yang F, Liu Z, Wang J, Huang W, Meng W, Billadeau DD, Sun Q, Mo X, Jia D. Structure of TBC1D23 N-terminus reveals a novel role for rhodanese domain. PLoS Biol. 2020;18:e3000746. [PMC free article: PMC7274447] [PubMed: 32453802]
• Liu Y, Yan X, Zhou T. TBCK influences cell proliferation, cell size and mTOR signaling pathway. PLoS One. 2013;8:e71349. [PMC free article: PMC3747267] [PubMed: 23977024]
• Mandel H, Khayat M, Chervinsky E, Elpeleg O, Shalev S. TBCK-related intellectual disability syndrome: case study of two patients. Am J Med Genet A. 2017;173:491-4. [PubMed: 27748029]
• Manickam K, McClain MR, Demmer LA, Biswas S, Kearney HM, Malinowski J, Massingham LJ, Miller D, Yu TW, Hisama FM; ACMG Board of Directors. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23:2029-37. [PubMed: 34211152]
• Mastromoro G, Guadagnolo D, Gianno F, Khaleghi Hashemian N, Terracciano A, Bernardini L, Giancotti A, Novelli A, Piacentini G, Di Gioia C, Pizzuti A. Cardiac involvement and TBCK-related neurodevelopmental disorder: is it a new feature of this condition? Am J Med Genet A. 2025;197:e64001. [PubMed: 39865381]
• Moreira DP, Suzuki AM, Silva A, Varella-Branco E, Meneghetti MCZ, Kobayashi GS, Fogo M, Ferrari MFR, Cardoso RR, Lourenco NCV, Griesi-Oliveira K, Zachi EC, Bertola DR, Weinmann KS, de Lima MA, Nader HB, Sertie AL, Passos-Bueno MR. Neuroprogenitor cells from patients with TBCK encephalopathy suggest deregulation of early secretory vesicle transport. Front Cell Neurosci. 2022:15:803302 [PMC free article: PMC8793280] [PubMed: 35095425]
• Murdock DR, Dai H, Burrage LC, Rosenfeld JA, Ketkar S, Muller MF, Yepez VA, Gagneur J, Liu P, Chen S, Jain M, Zapata G, Bacino CA, Chao HT, Moretti P, Craigen WJ, Hanchard NA, Undiagnosed Diseases N, Lee B. Transcriptome-directed analysis for mendelian disease diagnosis overcomes limitations of conventional genomic testing. J Clin Invest. 2021;131:e141500. [PMC free article: PMC7773386] [PubMed: 33001864]
• Ortiz-González XR, Tintos-Hernandez JA, Keller K, Li X, Foley AR, Bharucha-Goebel DX, Kessler SK, Yum SW, Crino PB, He M, Wallace DC, Bonnemann CG. Homozygous boricua TBCK mutation causes neurodegeneration and aberrant autophagy. Ann Neurol. 2018;83:153-65. [PMC free article: PMC5876123] [PubMed: 29283439]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Sabanathan S, Gulhane D, Mankad K, Davison J, Ong MT, Phadke R, Robinson R, Spiller M, Wakeling E, Ramdas S, Brady AF, Balasubramanian M, Munot P. Expanding the phenotype of children presenting with hypoventilation with biallelic TBCK pathogenic variants and literature review. Neuromuscul Disord. 2023;33:50-7. [PubMed: 36522252]
• Saredi S, Cauley ES, Ruggieri A, Spivey TM, Ardissone A, Mora M, Moroni I, Manzini MC. Myopathic changes associated with psychomotor delay and seizures caused by a novel homozygous mutation in TBCK. Muscle Nerve. 2020;62:266-71. [PMC free article: PMC7369155] [PubMed: 32363625]
• Schuhmacher JS, Tom Dieck S, Christoforidis S, Landerer C, Davila Gallesio J, Hersemann L, Seifert S, Schäfer R, Giner A, Toth-Petroczy A, Kalaidzidis Y, Bohnsack KE, Bohnsack MT, Schuman EM, Zerial M. The Rab5 effector FERRY links early endosomes with mRNA localization. Mol Cell. 2023;83:1839-1855.e13. [PubMed: 37267905]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Sumathipala D, Stromme P, Gilissen C, Corominas J, Frengen E, Misceo D. TBCK encephaloneuropathy with abnormal lysosomal storage: use of a structural variant bioinformatics pipeline on whole-genome sequencing data unravels a 20-year-old clinical mystery. Pediatr Neurol. 2019;96:74-5. [PubMed: 30898414]
• Tan HY, Wang B, Song YZ. Identification of a novel pathogenic TBCK variant in a Chinese patient with infantile hypotonia with psychomotor retardation and characteristic facies type 3 (IHPRF3): a case report. BMC Pediatr. 2022;22:612. [PMC free article: PMC9587582] [PubMed: 36273129]
• Tintos-Hernández JA, Santana A, Keller KN, Ortiz-González XR. Lysosomal dysfunction impairs mitochondrial quality control and is associated with neurodegeneration in TBCK encephaloneuronopathy. Brain Commun. 2021;3:fcab215. [PMC free article: PMC8603245] [PubMed: 34816123]
• Tsang MHY, Kwong AKY, Chan KLS, Fung JLF, Yu MHC, Mak CCY, Yeung KS, Rodenburg RJT, Smeitink JAM, Chan R, Tsoi T, Hui J, Wong SSN, Tai SM, Chan VCM, Ma CK, Fung STH, Wu SP, Chak WK, Chung BHY, Fung CW. Delineation of molecular findings by whole-exome sequencing for suspected cases of paediatric-onset mitochondrial diseases in the Southern Chinese population. Hum Genomics. 2020;14:28. [PMC free article: PMC7488033] [PubMed: 32907636]
• van der Sanden BPGH, Schobers G, Corominas Galbany J, Koolen DA, Sinnema M, van Reeuwijk J, Stumpel CTRM, Kleefstra T, de Vries BBA, Ruiterkamp-Versteeg M, Leijsten N, Kwint M, Derks R, Swinkels H, den Ouden A, Pfundt R, Rinne T, de Leeuw N, Stegmann AP, Stevens SJ, van den Wijngaard A, Brunner HG, Yntema HG, Gilissen C, Nelen MR, Vissers LELM. The performance of genome sequencing as a first-tier test for neurodevelopmental disorders. Eur J Hum Genet. 2023;31:81-88. [PMC free article: PMC9822884] [PubMed: 36114283]
• Zapata-Aldana E, Kim DD, Remtulla S, Prasad C, Nguyen C-T, Campbell C. Further delineation of TBCK - infantile hypotonia with psychomotor retardation and characteristic facies type 3. Eur J Med Genet. 2019;62:273-7. [PubMed: 30103036]