| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.3 | Hypopigmentation, organomegaly, and delayed myelination and development | 618541 | Autosomal dominant | 3 | CLCN7 | 602727 |
A number sign (#) is used with this entry because of evidence that hypopigmentation, organomegaly, and delayed myelination and development (HOD) is caused by heterozygous mutation in the CLCN7 gene (602727) on chromosome 16p13.
Hypopigmentation, organomegaly, and delayed myelination and development (HOD) is characterized by hypopigmented skin and hair with normally pigmented irides; organomegaly including enlargement of liver, kidney, and spleen; and delayed myelination on brain MRI accompanied by developmental delay in both gross and fine motor skills. Biopsy findings from skin and other organs are consistent with a lysosomal storage disorder (Nicoli et al., 2019).
Nicoli et al. (2019) reported 2 unrelated children, a 22-month-old Caucasian girl (patient 1) and a 14-month-old Ghanaian boy (patient 2), who had hypopigmented hair and skin but normally pigmented irides. Growth and development were delayed, and brain MRIs in both probands showed delayed myelination, thin posterior corpus callosum, hyperintensity of the subthalamic nuclei, and cerebellar atrophy. The probands also exhibited organomegaly involving the liver, kidneys, and spleen; biopsies were suggestive of a lysosomal storage disorder, with amorphous floccular storage material observed in hepatic macrophages and duodenal histiocytes from patient 1, as well as abnormal cytoplasmic inclusions in the skin. Transmission electron micrography of renal tissue from patient 2 showed numerous interstitial macrophages containing abundant cytoplasmic inclusions. Neither patient exhibited dysostosis multiplex or osteopetrosis.
The heterozygous mutations in the CLCN7 gene that were identified in patients with HOD by Nicoli et al. (2019) occurred de novo.
In 2 unrelated children with hypopigmentation, organomegaly, and delayed myelination and development, Nicoli et al. (2019) performed exome sequencing and identified heterozygosity for the same missense mutation in the CLCN7 gene (Y715C; 602727.0007) in both probands. The mutation arose de novo in both cases, and was not found in public variant databases.
Nicoli, E.-R., Weston, M. R., Hackbarth, M., Becerril, A., Larson, A., Zein, W. M., Baker, P. R., II, Burke, J. D., Dorward, H., Davids, M., Huang, Y., Adams, D. R., and 15 others. Lysosomal storage and albinism due to effects of a de novo CLCN7 variant on lysosomal acidification. Am. J. Hum. Genet. 104: 1127-1138, 2019. [PubMed: 31155284] [Full Text: https://doi.org/10.1016/j.ajhg.2019.04.008]