Truncating de novo mutations in the Krüppel-type zinc-finger gene ZNF148 in patients with corpus callosum defects, developmental delay, short stature, and dysmorphisms.
BACKGROUND
Krüppel-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.


METHODS
Routine diagnostic exome sequencing data were obtained from 2172 patients with ID and/or multiple congenital anomalies.


RESULTS
In 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.


CONCLUSIONS
We 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.
['Stevens|Servi J C|SJ|', 'van Essen|Anthonie J|AJ|', 'van Ravenswaaij|Conny M A|CM|', 'Elias|Abdallah F|AF|', 'Haven|Jaclyn A|JA|', 'Lelieveld|Stefan H|SH|', 'Pfundt|Rolph|R|', 'Nillesen|Willy M|WM|', 'Yntema|Helger G|HG|', 'van Roozendaal|Kees|K|', 'Stegmann|Alexander P|AP|', 'Gilissen|Christian|C|', 'Brunner|Han G|HG|']
D061085:Agenesis of Corpus Callosum D001483:Base Sequence D057215:Body Dysmorphic Disorders D002648:Child D004268:DNA-Binding Proteins D002658:Developmental Disabilities D005260:Female D006801:Humans D007231:Infant, Newborn D008297:Male D017384:Sequence Deletion D014157:Transcription Factors
De novo mutations ZNF148 Intellectual disability Whole exome sequencing Premature termination codon Corpus callosum development ZBP-89