PHF8 – Siderius X-linked intellectual disability syndrome

PHF8 is an X-linked gene encoding a plant homeodomain (PHD) finger and JmjC demethylase domain, and its loss-of-function causes Siderius X-linked intellectual disability syndrome (PHF8-XLID) (PHF8; Siderius X-linked intellectual disability syndrome). Affected males present with global developmental delay, borderline to severe intellectual disability, craniofacial dysmorphology, and neurobehavioral features such as autism spectrum disorder and attention deficit hyperactivity disorder.

Inheritance follows an X-linked recessive pattern. Initial reports described eight unrelated males with truncating PHF8 variants; a recent cohort adds 16 additional affected individuals from 11 unrelated families, all carrying predicted loss-of-function alleles ([PMID:35469323]). All affected males exhibited developmental delay and intellectual disability, with frequent hypertelorism, microcephaly, elongated face, and ptosis.

Variant spectrum is dominated by loss-of-function changes, including frameshift and nonsense mutations, as well as rare missense alleles. A representative variant is c.257C>T (p.Thr86Met), which segregates with disease in an affected family ([PMID:35469323]).

Functional studies confirm that PHF8 is a Fe(II)/2-oxoglutarate-dependent histone demethylase selective for H3K9me2/1, requiring its PHD finger for chromatin recruitment. Expression analyses show ubiquitous transcription with strong neural enrichment, and patient truncating mutants abolish catalytic activity ([PMID:16199551]; [PMID:20421419]).

The mechanism of pathogenicity is haploinsufficiency: loss of PHF8 demethylase activity impairs neuronal gene regulation and midline craniofacial development. Experimental models demonstrate that PHF8 deficiency disrupts histone methylation and neuronal differentiation concordant with human phenotypes.

Collectively, strong genetic and moderate functional evidence support PHF8 haploinsufficiency as the cause of Siderius XLID. PHF8 genetic testing enables accurate diagnosis and counseling in families with syndromic X-linked intellectual disability.

References

• HGG advances • 2022 • Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology. PMID:35469323
• Journal of medical genetics • 2005 • Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. PMID:16199551
• Molecular and cellular biology • 2010 • PHF8 targets histone methylation and RNA polymerase II to activate transcription. PMID:20421419

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