TBCK – Hypotonia, infantile, with psychomotor retardation and characteristic facies 3

TBCK encodes a TBC1 domain–containing kinase involved in Rab GTPase regulation, actin cytoskeleton dynamics and mTOR signaling. Biallelic loss‐of‐function or critical missense variants in TBCK cause autosomal recessive hypotonia, infantile, with psychomotor retardation and characteristic facies 3 (IHPRF3), characterized by profound developmental delay, hypotonia and dysmorphic facies ([PMID:27040692]).

Initial delineation of IHPRF3 in four unrelated families (n ≥ 4 probands) identified two truncating variants (c.376C>T (p.Arg126Ter), c.1363A>T (p.Lys455Ter)) and one missense variant (c.1532G>A (p.Arg511His)) disrupting the TBC domain, with confirmed loss of the major TBCK isoform in patient fibroblasts and in silico evidence of impaired Rab‐GAP activity ([PMID:27040692]).

A subsequent cohort of eight Puerto Rican children homozygous for c.376C>T (p.Arg126Ter) demonstrated progressive hypotonia, leukoencephalopathy, seizures, dysgenesis of the corpus callosum and motor neuronopathy. TBCK−/− fibroblasts exhibited increased LC3+ autophagosomes and autophagic flux, remediable by mTORC1 activation with leucine ([PMID:29283439]).

Further review of 33 additional IHPRF3 cases established a spectrum of pathogenic TBCK variants—predominantly frameshift and splice‐site mutations—with uniform neurodevelopmental progression and trend toward brain atrophy and facial dysmorphism, supporting a neurodegenerative mechanism ([PMID:30103036]).

In a 2025 report, three sibs from a consanguineous kindred homozygous for c.1532G>A (p.Arg511His) presented with classic IHPRF3 features plus novel cardiac malformations: right aortic arch, Tetralogy of Fallot, cystic hygroma and corpus callosum agenesis. Cardiac defects segregated with the TBCK variant, expanding the phenotypic spectrum to include congenital heart involvement ([PMID:39865381]).

Functional screening in zebrafish using tbck morpholinos revealed a critical role in atrioventricular canal formation, linking TBCK deficiency to heart development ([PMID:36574072]). A human neuronal model demonstrated TBCK’s role in endolysosomal mRNA trafficking and lysosomal axonal transport, implicating compartment‐specific trafficking defects in TBCKE pathogenesis ([PMID:40093117]).

Mechanism of pathogenicity involves loss of Rab‐GAP activity leading to mTORC1 inhibition, dysregulated autophagy and progressive neurodegeneration, now with documented cardiac involvement. Key take‐home: Biallelic TBCK variants definitively cause IHPRF3, with autosomal recessive inheritance and expanding cardiac phenotype warranting inclusion of cardiac screening in diagnostic work‐ups.

References

• American journal of human genetics • 2016 • Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy. PMID:27040692
• Ann Neurol • 2018 • Homozygous boricua TBCK mutation causes neurodegeneration and aberrant autophagy. PMID:29283439
• European journal of medical genetics • 2019 • Further delineation of TBCK - Infantile hypotonia with psychomotor retardation and characteristic facies type 3. PMID:30103036
• Cellular and molecular life sciences : CMLS • 2022 • Functional screening of congenital heart disease risk loci identifies 5 genes essential for heart development in zebrafish. PMID:36574072
• American journal of medical genetics. Part A • 2025 • Cardiac Involvement and TBCK-Related Neurodevelopmental Disorder: Is It a New Feature of This Condition? PMID:39865381

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