CLCN6

Inheritance Pattern: AD

Disease ID:MONDO:0030947

Submitter: ClinGen

*CLCN6* was first reported in relation to autosomal dominant condition, “neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities” in 2020 (Polovitskaya et al., PMID: 33217309). This gene encodes a Cl-/H+ antiporter that is primarily expressed in neuronal cells and localizes to late endosome-lysosome compartments (PMID: 16950870, 33708769, 17534424). The voltage-dependent Cl- /H+ exchanger activity of *CLCN6* is pH-dependent and relies on a V-ATPase pump to maintain acidic homeostasis within these compartments (PMID: 20466723, 37831762). To date, three unique missense variants have been identified in six unrelated individuals across four publications (PMID: 33217309, 37831762; 33590434, 38877824). Affected individuals presented severe global developmental delays, regression, generalized hypotonia, abnormal brain imaging, respiratory insufficiency, vision impairment, and feeding difficulties. Additional features include seizures, neurogenic bladder, short stature, microcephaly, temperature dysregulation, skin anomalies, neuropathy, and variable craniofacial dysmorphism. The *CLCN6* c.761T>C (p.Phe254Ser) reported as de novo in one male with neurodevelopmental disorder (PMID: 31785879) was not curated at this time due to lack of detailed clinical description and experimental investigations. The reported pathogenic mechanism involves a gain of function effect. Electrophysiological analyses demonstrated that both the p.Tyr553Cys and p.Thr520Ala variants induce larger, steady currents by selectively transporting Cl- independently of the acidic environment, using energy provided by ATP pumps at lower voltages compared to the wild type (PMID: 33217309, 37831762). Overexpression of these variants in Hela cells leads to the formation of giant cytoplasmic vacuoles resulting from the fusion of multiple small vesicles over time. These vacuoles exhibit reduced acidity, impaired endocytosis, and defective incorporation of lysosomal enzymes (PMID: 33217309, 37831762). Experimental studies of the p.Glu200Ala (E200A) variant demonstrated similar disruption of the lysosomal functions. Heterologous expression of this variant in Xenopus does not alter *CLCN6* localization but blocks proton transposition, resulting in a change in Cl-/H+ exchanger activity (PMID: 20466723). In the presence of this *CLCN6* variant, cytoplasmic vesicles are mildly enlarged and fail to incorporate lysosomal enzymes. Additionally, the mutant increases autophagosome accumulation by inhibiting autophagosome degradation and fusion with the lysosome (PMID: 33590434, 38877824). The phenotype of the *CLCN6* E200A/+ knock in mice largely recapitulated the human disease including tremor, seizures, ataxia, motor abnormalities, brain atrophy, enlarged ventricles, behavioral abnormalities, and premature death. Experimental studies further revealed abnormal accumulation of lysosomal material, along with enlarged lysosomes. These alterations were likely caused by reduced mTORC1 activity, which promoted nuclear translocation of the transcriptional regulators TFEB and TFE3. This activation enhanced the expression of autophagy- lysosome related proteins, including LC3, p62, LAMP1, and CTSD. Collectively, these findings indicated defective autophagic and lysosomal turnover, leading to increased apoptosis and potentially explaining the neuronal loss observed in the KI mouse brain (PMID: 38877824). In summary, there is moderate evidence supporting the relationship between *CLCN6* and “neurodegeneration, childhood-onset, hypotonia, respiratory insufficiency and brain imaging abnormalities”. Of note, this classification only focuses on gain-of-function mechanisms while loss-of-function mechanisms reportedly associated with mild neuronal ceroid lipofuscinosis in mice model (PMID: 16950870, 38877824) and frontotemporal dementia (PMID: 33737586) were not curated in this entry. This classification was approved by the ClinGen Lysosomal Diseases GCEP on May 7, 2024 (SOP Version 10). It was reevaluated on 06/12/2026 with new evidence and the classification remained Moderate.

Inheritance Pattern: AD

Disease ID:MONDO:0030947

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0030947

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0030947

Submitter: Ambry Genetics