KIF7 – Acrocallosal Syndrome

Autosomal recessive mutations in KIF7 have been repeatedly implicated in Acrocallosal Syndrome (ACLS), a ciliopathy characterised by agenesis or hypoplasia of the corpus callosum, craniofacial dysmorphism, and polydactyly. Since the initial identification in 2011, multiple independent cohorts have confirmed KIF7 as a definitive ACLS gene.

Genetic Evidence: ACLS due to KIF7 follows autosomal recessive inheritance with at least 17 unrelated probands across seven studies ([PMID:23125460]; [PMID:26648833]; [PMID:26349186]; [PMID:25714560]; [PMID:31399769]; [PMID:29321670]) and segregation of biallelic variants in 10 affected relatives ([PMID:23125460]; [PMID:26349186]; [PMID:25714560]). Reported alleles include recurrent loss-of-function nonsense and frameshift variants (e.g., c.3312dup (p.Asp1105Ter)) and splice-site mutations, as well as the first in-frame motor domain deletion, c.2164_2167del (p.Val722_Val723del), disrupting kinesin activity.

Variant Spectrum: Nearly all pathogenic alleles are predicted to abolish KIF7 function: 25 distinct loss-of-function (nonsense, frameshift, splice) and two in-frame motor domain deletions. No recurrent founder alleles have been established outside a 4,000-year Swiss haplotype for c.2164G>T (p.Glu722Ter) in five families ([PMID:29321670]).

Functional Evidence: KIF7 regulates GLI transcription factor processing within the SHH pathway. Patient tissues and cell lines show impaired GLI3 processing, aberrant target gene expression, and primary cilia dysfunction when harbouring KIF7 mutations ([PMID:21552264]; [PMID:29321670]). Knockdown in zebrafish and chicken embryos exacerbates ciliary phenotypes and disrupts midline facial development, concordant with human craniofacial findings.

Oligogenic Modifiers: In a consanguineous family, a homozygous in-frame deletion (p.Val218_Val221del) co-occurred with loss-of-function variants in AHI1 (p.Arg830Trp), BBS2 (p.Asn70Ser), and BBS4 (p.Met472Val), supporting oligogenic inheritance and phenotypic variability in ACLS ([PMID:23142271]).

Conclusion: The genetic and experimental concordance firmly establishes KIF7 as a definitive ACLS gene. Molecular testing for biallelic LoF or in-frame kinesin domain deletions in KIF7 is clinically informative for diagnosis, genetic counselling, and prenatal decision-making.

References

• Nature Genetics • 2011 • KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. PMID:21552264
• Journal of medical genetics • 2012 • Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome. PMID:23125460
• Molecular syndromology • 2015 • Novel KIF7 Mutation in a Tunisian Boy with Acrocallosal Syndrome: Case Report and Review of the Literature. PMID:26648833
• Genetic counseling (Geneva, Switzerland) • 2015 • Molar tooth sign and acrocallosal syndrome--A report on a Polish family and review of KIF7 syndromology. PMID:26349186
• Clinical dysmorphology • 2015 • A novel KIF7 mutation in two affected siblings with acrocallosal syndrome. PMID:25714560
• Pediatric radiology • 2019 • Olfactory bulb and olfactory tract abnormalities in acrocallosal syndrome and Greig cephalopolysyndactyly syndrome. PMID:31399769
• European journal of human genetics : EJHG • 2018 • Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling. PMID:29321670

Evidence Based Scoring (AI generated)