HCFC1 – X-linked intellectual disability

HCFC1, a global transcriptional regulator, has been implicated in X-linked intellectual disability distinct from cobalamin metabolism disorders. Pathogenic variants outside the Kelch domain disrupt neurodevelopmental pathways without causing methylmalonic acidemia or hyperhomocysteinemia ([PMID:33517344]).

Genetic evidence includes a regulatory mutation in the YY1 binding site leading to HCFC1 overexpression in family MRX3 ([PMID:23000143]), two male siblings with c.2690C>T (p.Ala897Val) presenting ID and microcephaly without cobalamin defects ([PMID:26893841]), and two individuals harboring missense c.1429G>A (p.Ala477Thr) and c.1583C>T (p.Pro528Leu) showing partial loss-of-function in neural assays ([PMID:25740848]). A recent family of five (three males, two females) carries a maternally inherited splice‐disrupting c.1784_1803del (p.Val595GlyfsTer?) variant with co-segregation and skewed X-inactivation in manifesting females ([PMID:33517344]). A novel hemizygous c.5705G>A (p.Ser1902Asn) variant was also identified in a Pakistani pedigree with co-segregation and developmental delay ([PMID:38956580]).

Inheritance is X-linked recessive with 3 additional affected relatives confirmed by segregation (2 half-siblings, 1 great-uncle). The variant spectrum comprises noncoding regulatory (c.-970T>C), missense (p.Ala477Thr, p.Pro528Leu, p.Ala897Val, p.Ser1902Asn), and predicted loss-of-function splice/frameshift variants (c.1784_1803del (p.Val595GlyfsTer?)). No recurrent founder alleles have been reported. Clinically, patients exhibit global developmental delay (HP:0001263) with intellectual disability and mild dysmorphic features, uniformly lacking metabolic abnormalities.

Functional assays demonstrate that regulatory mutations increase HCFC1 expression, altering astrocyte differentiation and neurite outgrowth in murine neural cells ([PMID:23000143]). Splice-site disruption causing exon 10 skipping was validated by cDNA sequencing and in silico models ([PMID:33517344]). Loss-of-function studies using shRNA in embryonic neural progenitors favor proliferation over differentiation and enhance axonal growth impairments, rescued by wild-type HCFC1 ([PMID:25740848]). These data converge on a haploinsufficiency mechanism affecting neural development.

No studies have refuted this association; metabolic testing consistently shows normal methylmalonic and homocysteine levels in ID-only cases. Phenotypic variability in females is attributed to X-inactivation skewing.

Collectively, multiple unrelated families with co-segregating HCFC1 variants and concordant functional data support a Strong gene-disease association. HCFC1 should be included in diagnostic panels for X-linked intellectual disability, particularly when cobalamin metabolism is unremarkable. Key take-home: HCFC1 variants outside the Kelch domain underlie a distinct form of X-linked intellectual disability with clear clinical utility in genetic testing.

References

• Journal of human genetics • 2021 • Novel exon-skipping variant disrupting the basic domain of HCFC1 causes intellectual disability without metabolic abnormalities in both male and female patients. PMID:33517344
• American journal of human genetics • 2012 • A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability. PMID:23000143
• Human molecular genetics • 2015 • HCFC1 loss-of-function mutations disrupt neuronal and neural progenitor cells of the developing brain. PMID:25740848
• Biomedical reports • 2016 • A novel HCFC1 variant in male siblings with intellectual disability and microcephaly in the absence of cobalamin disorder. PMID:26893841
• BMC medical genomics • 2024 • Variants in HCFC1 and MN1 genes causing intellectual disability in two Pakistani families. PMID:38956580

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