@article {762, title = {Post-zygotic ACTB mutations underlie congenital smooth muscle hamartomas.}, journal = {J Cutan Pathol}, volume = {47}, year = {2020}, month = {2020 Aug}, pages = {681-685}, abstract = {

BACKGROUND: Congenital smooth muscle hamartomas (CSMHs) are benign lesions that share clinical and histopathological features with Becker nevus, a mosaic disorder associated with post-zygotic ACTB mutations. Given the clinical and histopathological overlap between CSMH and Becker nevus, we hypothesized that post-zygotic mutations in ACTB may underlie CSMH.

METHODS: Direct sequencing of ACTB gene in affected and unaffected tissue isolated from one case of hemihypertrichosis and hemihypertrophy corresponding to giant segmental CSMH and hemihypertrophy. This was followed by direct sequencing with and without enrichment assay for hotspot ACTB mutations in affected tissue from 12 samples of isolated CSMH from unrelated individuals.

RESULTS: In total we identified somatic missense ACTB mutations in 9 out of 13 CSMHs (69\%). Mutations were either novel or previously reported in Becker nevi and Becker nevus syndrome.

CONCLUSIONS: CSMHs result from post-zygotic ACTB mutations. This study proves that CSMHs and Becker nevi are nosologically related, and expand the phenotypic spectrum of ACTB mutations.

}, issn = {1600-0560}, doi = {10.1111/cup.13683}, author = {Atzmony, Lihi and Ugwu, Nelson and Zaki, Theodore D and Antaya, Richard J and Choate, Keith A} } @article {700, title = {Phenotypic expansion of POFUT1 loss of function mutations in a disorder featuring segmental dyspigmentation with eczematous and folliculo-centric lesions.}, journal = {Am J Med Genet A}, volume = {179}, year = {2019}, month = {2019 Dec}, pages = {2469-2473}, abstract = {

Appearance of mosaic disorders in thin Blaschko lines suggests that somatic mutations in keratinocyte precursors underlie their pathogenesis. Germline heterozygous mutations in POFUT1 gene cause Dowling-Degos disease (DDD), a skin disease that features flexural reticulated hyperpigmentation and follicular-based lesions. POFUT1 mosaicism has not been described to date. Here, we describe a 9-year-old female with segmental hyper- and hypopigmented patches with overlying eczematous plaques and follicular papules. Employing paired whole exome sequencing of saliva and keratinocytes isolated from affected skin, we found a novel germline heterozygous POFUT1 deletion causing frameshift and premature codon termination and somatic copy-neutral loss of heterozygosity on chromosome 20 encompassing POFUT1. Expression levels of POFUT1 as well as other key regulators of the notch signaling pathway-NOTCH1, NOTCH2, and HES1-were reduced in affected keratinocytes compared with normal keratinocytes. Our findings provide the first evidence of POFUT1 postzygotic mutation and a phenotypic expansion of POFUT1 loss of function mutations. We show that a recessive loss of function mutation in POFUT1 produces a distinct clinical presentation with features (e.g., dermatitis) that are absent in the generalized form of DDD. This study demonstrates how analysis of mosaic disorders can reveal unexpected phenotypes for known genes.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61362}, author = {Atzmony, Lihi and Zaki, Theodore D and Antaya, Richard J and Choate, Keith A} }