SETD5 – Intellectual Disability-Facial Dysmorphism Syndrome due to SETD5 Haploinsufficiency

SETD5 encodes a SET domain–containing protein involved in chromatin regulation. Haploinsufficiency of SETD5 is associated with an autosomal dominant neurodevelopmental syndrome characterized by intellectual disability and facial dysmorphism (MONDO:0014336).

Multiple unrelated individuals have been identified with de novo loss-of-function variants in SETD5, supporting pathogenic haploinsufficiency. A prenatal case presented with first-trimester cystic hygroma and later developed intellectual disability; exome sequencing revealed a de novo c.646del (p.Gln216SerfsTer35) variant (PMID:33218422). A 10-year-old boy with intellectual disability and facial dysmorphism harbored a de novo splice variant c.960-5C>G (PMID:28905509). In an Indian neurodevelopmental cohort, a de novo nonsense variant c.1967T>G (p.Leu656Ter) was reported in a patient with syndromic intellectual disability (PMID:38114583). No familial segregation beyond de novo occurrence has been described.

All reported variants are predicted loss-of-function (frameshift, essential splice site, nonsense), consistent with a haploinsufficiency mechanism. No recurrent or founder alleles have been documented to date.

Functional studies in zebrafish and mouse models demonstrate that Setd5 haploinsufficiency impairs neural progenitor proliferation, synaptic wiring, and behavioral outputs, mirroring human neurodevelopmental phenotypes (PMID:31515109). Additional cellular studies reveal that SETD5 deficiency disrupts promoter-proximal RNA polymerase II pausing and global transcriptional fidelity, supporting a mechanistic basis for intellectual disability (PMID:34853439).

No studies have refuted the SETD5–MONDO:0014336 association. The convergence of de novo loss-of-function variants and concordant functional data yields a moderate level of evidence for clinical validity.

Key take-home: De novo loss-of-function variants in SETD5 cause an autosomal dominant intellectual disability-facial dysmorphism syndrome via haploinsufficiency; SETD5 should be included in neurodevelopmental disorder gene panels and prenatal diagnostic considerations.

References

• Taiwanese journal of obstetrics & gynecology • 2020 • First-trimester cystic hygroma and neurodevelopmental disorders: The association to remember. PMID:33218422
• American journal of medical genetics. Part A • 2017 • De novo SETD5 loss-of-function variant as a cause for intellectual disability in a 10-year old boy with an aberrant blind ending bronchus. PMID:28905509
• Neuron • 2019 • SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring. PMID:31515109
• Leukemia • 2022 • SETD5 modulates homeostasis of hematopoietic stem cells by mediating RNA Polymerase II pausing in cooperation with HCF-1. PMID:34853439
• European journal of human genetics : EJHG • 2024 • De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India. PMID:38114583

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