Lee CL et al. (2024), Multisystem disorder associated with a pathogen...

XB-ART-60836

Mol Genet Genomic Med 2024 Jul 01;127:e2494. doi: 10.1002/mgg3.2494.

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Multisystem disorder associated with a pathogenic variant in CLCN7 in the absence of osteopetrosis.

Lee CL , Chang YW , Lin HY , Lee HC , Yeh TC , Fang LC , Lee NC , Tsai JD , Lin SP .

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BACKGROUND: We clinically and genetically evaluated a Taiwanese boy presenting with developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation without osteopetrosis. Whole-exome sequencing revealed a de novo gain-of-function variant, p.Tyr715Cys, in the C-terminal domain of ClC-7 encoded by CLCN7. METHODS: Nicoli et al. (2019) assessed the functional impact of p.Tyr715Cys by heterologous expression in Xenopus oocytes and evaluating resulting currents. RESULTS: The variant led to increased outward currents, indicating it underlies the patient's phenotype of lysosomal hyperacidity, storage defects and vacuolization. This demonstrates the crucial physiological role of ClC-7 antiporter activity in maintaining appropriate lysosomal pH. CONCLUSION: Elucidating mechanisms by which CLCN7 variants lead to lysosomal dysfunction will advance understanding of genotype-phenotype correlations. Identifying modifier genes and compensatory pathways may reveal therapeutic targets. Ongoing functional characterization of variants along with longitudinal clinical evaluations will continue advancing knowledge of ClC-7's critical roles and disease mechanisms resulting from its dysfunction. Expanded cohort studies are warranted to delineate the full spectrum of associated phenotypes.

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Species referenced: Xenopus laevis
Genes referenced: clcn7 ostm1

???displayArticle.disOnts??? congenital hypogammaglobulinemia

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	FIGURE 1 Clinical and radiological findings in the patient. (a) Patient showing hypopigmentation of the skin and hair. (a1) Birth (a2) 2-year-old (b) Abdominal ultrasonography demonstrating diffuse and homogeneous increased echogenicity of the liver. (c) Renal ultrasonography showing bilateral nephromegaly with increased echogenicity and poor corticomedullary differentiation.
	FIGURE 2 Peripheral blood smear from the proband demonstrating lymphocytosis with atypical lymphocyte morphology (Wright-Giemsa stain). (a) and (b) High magnification images (100× oil immersion) showing reactive lymphocytes with lobulated nuclei and numerous cytoplasmic vacuoles of varying sizes (indicated by arrows).
	FIGURE 3 Targeted Sanger sequencing was also performed on DNA extracted from blood samples of family members.
	FIGURE 1. Clinical and radiological findings in the patient. (a) Patient showing hypopigmentation of the skin and hair. (a1) Birth (a2) 2‐year‐old (b) Abdominal ultrasonography demonstrating diffuse and homogeneous increased echogenicity of the liver. (c) Renal ultrasonography showing bilateral nephromegaly with increased echogenicity and poor corticomedullary differentiation.
	FIGURE 2. Peripheral blood smear from the proband demonstrating lymphocytosis with atypical lymphocyte morphology (Wright‐Giemsa stain). (a) and (b) High magnification images (100× oil immersion) showing reactive lymphocytes with lobulated nuclei and numerous cytoplasmic vacuoles of varying sizes (indicated by arrows).
	FIGURE 3. Targeted Sanger sequencing was also performed on DNA extracted from blood samples of family members.