ZNF674 – X-linked Intellectual Disability

ZNF674 was first implicated in X-linked intellectual disability in a single pedigree presenting with cognitive impairment, short stature (HP:0004322), and retinal dystrophy (HP:0000556). A nonsense variant, c.337G>T (p.Glu113Ter), predicted to truncate all zinc-finger domains, was identified in one of 28 linked families (PMID:16385466). Sequencing of 306 additional XLID patients revealed only missense changes of uncertain significance without further segregation. Importantly, reanalysis of 10,563 control X chromosomes found the same truncating c.337G>T variant at appreciable frequency, challenging its pathogenicity (PMID:23871722). Functional support is limited to in silico modeling predicting reduced DNA binding. Overall, the genetic and experimental data are conflicting and insufficient, supporting a disputed classification for ZNF674 in XLID. Key Take-home: ZNF674 should not be routinely included in XLID diagnostic panels without additional corroborative evidence.

References

• 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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