ASPM – Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH; MONDO:0016660) is a neurodevelopmental disorder characterized by congenital reduction of occipito-frontal head circumference (OFC) below –2 SD with non-progressive intellectual disability. ASPM (abnormal spindle-like microcephaly associated; HGNC:19048) is the most frequently mutated gene in MCPH, accounting for 40–68% of cases across diverse populations (PMID:19770472).

Genetic analyses of over 450 unrelated families have identified biallelic loss-of-function (LoF) and splice-site variants in ASPM in autosomal recessive inheritance. In a large consanguineous Pakistani pedigree, a novel homozygous nonsense mutation c.7543C>T (p.Arg2515Ter) segregated with MCPH in all affected individuals and obligate carriers (PMID:29431480). Segregation analysis in 52 unrelated probands and 5 affected siblings further demonstrated consistent co-segregation of ASPM variants with MCPH phenotype (PMID:19770472).

Variant spectrum includes 161 distinct pathogenic mutations: 80% are truncating (nonsense, frameshift, splice-site), and ~20% are rare missense variants of uncertain significance. Recurrent or founder mutations (e.g., p.Trp1326Ter in Pakistani families) highlight population-specific screening strategies (PMID:27250695). The c.7543C>T (p.Arg2515Ter) variant exemplifies ASPM LoF through nonsense-mediated decay and underlies the MCPH5 phenotype in multiple ethnic groups.

Functional studies reveal that ASPM transcripts encode an 81-IQ-motif repeat protein that localizes to mitotic spindle poles in neuroprogenitor cells, regulating spindle orientation and symmetric division (PMID:15972725). Isoform analysis confirms that exon-skipping and alternative splicing alter IQ-motif number, potentially modulating cortical size. Cellular assays and mouse models consistently support a haploinsufficiency mechanism for ASPM-related MCPH.

No significant association has been observed between common ASPM polymorphisms (e.g., A44871G) and normal brain size or cognition in healthy cohorts, arguing against a dosage effect outside pathological truncating variants (PMID:17566767). No conflicting evidence disputes ASPM’s central role in MCPH.

In summary, extensive genetic and experimental data provide definitive evidence for ASPM as the primary gene underlying autosomal recessive primary microcephaly. Biallelic LoF mutations result in reduced neuronal progenitor proliferation, leading to microcephaly and intellectual disability. ASPM genetic testing enables accurate diagnosis, carrier screening, and informed genetic counseling in MCPH families.

Key Take-home: ASPM loss-of-function mutations cause definitive MCPH5, supporting targeted genetic diagnostics and reproductive counseling.

References

• Neurology • 2009 • Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations PMID:19770472
• Genetic testing and molecular biomarkers • 2018 • Identification of a Novel Nonsense ASPM Mutation in a Large Consanguineous Pakistani Family Using Targeted Next-Generation Sequencing PMID:29431480
• Human molecular genetics • 2005 • The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein PMID:15972725
• American journal of medical genetics. Part A • 2016 • Molecular and phenotypic spectrum of ASPM-related primary microcephaly: Identification of eight novel mutations PMID:27250695
• NeuroImage • 2007 • Investigation of MCPH1 G37995C and ASPM A44871G polymorphisms and brain size in a healthy cohort PMID:17566767

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