ZNF674 – Intellectual Disability

ZNF674 encodes a Krüppel-associated box (KRAB) zinc-finger transcription factor implicated in cognitive development. A duplication encompassing ZNF674 was reported in a male with global developmental delay and intellectual disability ([PMID:20691945]). In families linked to nonsyndromic X-linked mental retardation, a nonsense variant c.337G>T (p.Glu113Ter) and a missense variant p.Pro412Leu, predicted to disrupt DNA-binding, were identified in independent probands ([PMID:16385466]). These findings support an X-linked recessive mechanism but lack segregation data beyond single families and functional validation is limited.

Contrastingly, large-scale exome sequencing studies have identified truncating variants in ZNF674 at appreciable frequencies in control X chromosomes, challenging its role as a monogenic XLID gene ([PMID:23871722]). The absence of robust in vitro or in vivo functional assays, combined with potential polymorphic occurrence of missense changes, limits definitive attribution. Key Take-home: current evidence for ZNF674 in intellectual disability is conflicting and should be interpreted cautiously in diagnostic settings.

References

• Pediatric neurology • 2010 • Developmental disability: duplication of zinc finger transcription factors 673 and 674. PMID:20691945
• American journal of human genetics • 2006 • ZNF674: a new kruppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation. PMID:16385466
• American journal of human genetics • 2013 • XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing. PMID:23871722

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