Two cases of autosomal recessive congenital ichthyosis due to CYP4F22 mutations: Expanding the genotype of self-healing collodion baby

Collodion babies are born with a tight, shiny cast that sheds in a few weeks. After shedding, most patients will display features of autosomal recessive congenital ichthyosis (ARCI) later in life but in up to 10% of cases, the skin eventually becomes normal or only minimally involved, a phenotype called self-healing collodion baby (SHCB), which is considered as ARCI subtype in the 2010 consensus classification of congenital ichthyosis. The term self-improving collodion ichthyosis (SICI) has been proposed for these patients. SHCB/SICI was initially associated with mutations in the gene TGM1. However, some cases showing ALOX12B and ALOXE3 gene mutations have also been reported. We report two cases of SHCB/SICI showing homozygous mutations in the gene CYP4F22.Peer Reviewe

Loss-of-function of the Zinc Finger Homeobox 4 (ZFHX4) gene causes a novel neurodevelopmental disorder

Neurodevelopmental disorders (NDDs) result from impaired development and functioning of the brain. Here, we identify a novel NDD caused by loss-of-function variation in ZFHX4, encoding a zinc-finger homeodomain transcription factor. In 2011, ZFHX4 haploinsufficiency was suggested as (one of) the underlying mechanism(s) in 8q21.11 microdeletions. Moreover, in 2020, ZFHX4 was reported as a novel NDD candidate gene in a large-scale exome-sequencing study. Through an international collaboration, we gathered data on 47 individuals with protein truncating variants (n=27), (micro)deletions (n=19) or an inversion (n=1) affecting ZFHX4. Loss-of-function of ZFHX4 consistently associates with ID, morphological abnormalities of the central nervous system, short stature, hypotonia and distinctive facial characteristics as supported by artificial intelligence (Face2Gene), and, occasionally, cleft palate and anterior segment dysgenesis. We identified a preliminary mild common DNA methylation profile in leukocyte-derived DNA of patients with truncating variants and with (micro)deletions affecting ZFHX4. Via data-mining and multiple in vitro models we identified ZFHX4 as a nuclear protein and found increasing expression during human brain development and neuronal differentiation. First-generation (F0) zfhx4 crispant zebrafish - (mosaic) mutant for zfhx4 loss-of-function variants - have significantly smaller Meckel’s cartilages and ethmoid plates in comparison with control zebrafish upon Alcian blue staining. To get a better understanding of its role during neurodevelopment, we are currently assessing the interaction partners and downstream targets of ZFHX4 in neural progenitor cells and neural crest cells. In conclusion, ZFHX4 appears to be essential for neural and craniofacial development and ZFHX4 loss-of-function variants are associated with a novel form of syndromic ID