Abstract
BackgroundKrüppel-type zinc finger genes (ZNF) constitute a large yet relatively poorly characterized gene family. ZNF genes encode proteins that recognize specific DNA motifs in gene promotors. They act as transcriptional co-activators or -repressors via interaction with chromatin remodeling proteins and other transcription factors. Only few ZNF genes are currently linked to human disorders and identification of ZNF gene-associated human diseases may help understand their function. Here we provide genetic, statistical, and clinical evidence to support association of ZNF148 with a new intellectual disability (ID) syndrome disorder.MethodsRoutine diagnostic exome sequencing data were obtained from 2172 patients with ID and/or multiple congenital anomalies.ResultsIn a cohort of 2172 patient–parent trios referred for routine diagnostic whole exome sequencing for ID and/or multiple congenital anomalies (MCA) in the period 2012–2016, four patients were identified who carried de novo heterozygous nonsense or frameshift mutations in the ZNF148 gene. This was the only ZNF gene with recurrent truncating de novo mutations in this cohort. All mutations resulted in premature termination codons in the last exon of ZNF148. The number of the de novo truncating mutations in the ZNF148 gene was significantly enriched (p = 5.42 × 10−3). The newly described ZNF148-associated syndrome is characterized by underdevelopment of the corpus callosum, mild to moderate developmental delay and ID, variable microcephaly or mild macrocephaly, short stature, feeding problems, facial dysmorphisms, and cardiac and renal malformations.ConclusionsWe propose ZNF148 as a gene involved in a newly described ID syndrome with a recurrent phenotype and postulate that the ZNF148 is a hitherto unrecognized but crucial transcription factor in the development of the corpus callosum. Our study illustrates the advantage of whole exome sequencing in a large cohort using a parent–offspring trio approach for identifying novel genes involved in rare human diseases.
Highlights
Krüppel-type zinc finger genes (ZNF) constitute a large yet relatively poorly characterized gene family
We identified truncating de novo mutations in the Zinc Finger Protein 148 (ZNF148; known as ZBP-89 or ZFP148) from a large cohort of patient–parents trios referred for diagnostic exome sequencing in the period 2012–2016
Clinical reports Patient 1 is a 6-year-old girl born at 35 + 4 weeks after an uncomplicated pregnancy who presented with respiratory insufficiency and severe feeding problems requiring gavage feeding
Summary
Krüppel-type zinc finger genes (ZNF) constitute a large yet relatively poorly characterized gene family. ZNF genes encode DNA-binding proteins, related to the archetypal Drosophila regulatory protein Krüppel, which recognizes specific DNA sequence motifs in gene promoters. They bind the major groove of the double helix by their C2H2 zinc finger domains, each consisting of a chain of two cysteines and two histidines that fold around and are stabilized by a single Zn2+ ion. We identified truncating de novo mutations in the Zinc Finger Protein 148 (ZNF148; known as ZBP-89 or ZFP148) from a large cohort of patient–parents trios referred for diagnostic exome sequencing in the period 2012–2016 These de novo mutations lead to syndromic intellectual disability (ID) with corpus callosum anomalies and short stature as shared features, accompanied by secondary variable microcephaly or mild macrocephaly, feeding problems, variable facial features, talipes, and malformations of the heart and kidneys
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