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Although one proposed study approach is to increase sensitivity by increasing sample sizes, another is to focus on families with multiple affected individuals to identify genes with rare or novel variants with strong effects. Choosing the family\u2010based approach, we performed whole\u2010exome analysis on affected individuals (n\u2009=\u200912) across five MDD families, each with at least five affected individuals, early onset, and prepubertal diagnoses. We identified 67 genes where novel deleterious variants were shared among affected relatives. Gene ontology analysis shows that of these 67 genes, 18 encode transcriptional regulators, eight of which are expressed in the human brain, including four KRAB\u2010A box\u2010containing Zn<jats:sup>2+<\/jats:sup> finger repressors. One of these, <jats:italic>ZNF34<\/jats:italic>, has been reported as being associated with bipolar disorder and as differentially expressed in bipolar disorder patients compared to healthy controls. We found a novel variant\u2014encoding a non\u2010conservative P17R substitution in the conserved repressor domain of ZNF34 protein\u2014segregating completely with MDD in all available individuals in the family in which it was discovered. Further analysis showed a common <jats:italic>ZNF34<\/jats:italic> coding indel segregating with MDD in a separate family, possibly indicating the presence of an unobserved, linked, rare variant in that particular family. Our results indicate that genes encoding transcription factors expressed in the brain might be an important group of MDD candidate genes and that rare variants in <jats:italic>ZNF34<\/jats:italic> might contribute to susceptibility to MDD and perhaps other affective disorders. \u00a9 2016 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.b.32408","type":"journal-article","created":{"date-parts":[[2016,1,29]],"date-time":"2016-01-29T07:48:26Z","timestamp":1454053706000},"page":"333-341","source":"Crossref","is-referenced-by-count":28,"title":["Novel variants in <i>ZNF34<\/i> and other brain\u2010expressed transcription factors are shared among early\u2010onset MDD relatives"],"prefix":"10.1002","volume":"171","author":[{"given":"Ryan L.","family":"Subaran","sequence":"first","affiliation":[{"name":"Nationwide Children's Hospital Columbus 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