KNL1 – Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by congenital reduction in brain size, nonprogressive cognitive impairment and absence of additional malformations. KNL1 (CASC5) encodes a core component of the KMN kinetochore network essential for microtubule attachment and spindle‐assembly checkpoint activation during mitosis. Pathogenic variants in KNL1 define MCPH4, underscoring the importance of kinetochore integrity in cortical development.

In 2012, a homozygous frameshift mutation causing exon 18 skipping and predicted protein truncation was identified in three consanguineous families with MCPH, achieving a combined LOD score >6 and segregating with disease status ([PMID:22983954]). Follow-up sequencing in North African cohorts revealed a recurrent founder missense variant, c.6125G>A (p.Met2041Ile), in three Moroccan and one Algerian family; affected individuals exhibited head circumference ≤-3 SD, moderate-to-severe cognitive impairment and short stature ([PMID:26626498]).

Additional patients carry diverse homozygous KNL1 variants, including frameshift (c.5184dup (p.Ile1729fs)), intronic splice (c.6673-19T>A) and missense changes (c.6482A>G (p.Asp2161Gly), c.6560A>G (p.Lys2187Arg)), confirming a spectrum of loss‐of‐function alleles in ≥10 probands from 7 families ([PMID:22983954]; [PMID:26626498]; [PMID:26621532]; [PMID:37937525]).

Functional studies in patient fibroblasts demonstrate downregulation of KNL1 mRNA and protein, mitotic arrest, dispersed kinetochore signals, lobulated nuclei, micronuclei formation and elevated DNA damage markers, indicating compromised chromosome segregation ([PMID:26621532]). In vitro neural differentiation of embryonic stem cells with patient mutations recapitulates brain‐specific reduction of KNL1, aneuploidy and spindle checkpoint failure, while non-neural cells remain unaffected ([PMID:30304678]). Moreover, splicing assays confirm exon 23 skipping due to an intronic variant, disrupting KMN complex interactions ([PMID:37937525]).

Collectively, the genetic and experimental data provide definitive evidence that biallelic KNL1 variants cause autosomal recessive primary microcephaly via loss of kinetochore function and haploinsufficiency during neurogenesis. Key Take-home: Inclusion of KNL1 in molecular diagnostic panels enables accurate genetic counselling and early diagnosis of MCPH4.

References

• Human molecular genetics • 2012 • Kinetochore KMN network gene CASC5 mutated in primary microcephaly. PMID:22983954
• Neurogenetics • 2016 • Refining the phenotype associated with CASC5 mutation. PMID:26626498
• Human genetics • 2016 • A novel homozygous splicing mutation of CASC5 causes primary microcephaly in a large Pakistani family. PMID:26621532
• Cell reports • 2018 • Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype. PMID:30304678
• American journal of medical genetics. Part A • 2024 • A novel KNL1 intronic splicing variant likely destabilizes the KMN complex, causing primary microcephaly. PMID:37937525

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