Normal early development in siblings with novel compound heterozygous variants in ASPM

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Autosomal recessive primary microcephaly 5 (MCPH5) is a rare genetic disorder characterized by reduced head circumference and brain size.
• Pathogenic variants in the ASPM gene are the known cause of MCPH5.
• The precise genotype-phenotype correlations in MCPH5, particularly concerning cognitive outcomes, remain incompletely understood.

Purpose of the Study:

• To diagnose and characterize MCPH5 in two siblings presenting with the condition.
• To identify the specific genetic variants in the ASPM gene responsible for MCPH5 in the affected siblings.
• To investigate the relationship between identified ASPM variants and the observed normal intelligence in the affected individuals.

Main Methods:

• Whole-exome sequencing was employed to analyze the genetic makeup of the affected siblings.
• Sanger sequencing or similar methods were used to confirm the identified variants.
• Clinical assessments were performed to evaluate the intelligence and neurological status of the siblings.

Main Results:

• Two siblings were diagnosed with Autosomal recessive primary microcephaly 5 (MCPH5).
• A known pathogenic variant (c.9697C>T, p.(Arg3233*)) and a novel pathogenic variant (c.1402_1406del, p.(Asn468Serfs*2)) in the ASPM gene were identified in the affected siblings.
• Despite the presence of these pathogenic variants, both siblings exhibited normal intelligence.

Conclusions:

• The study identified both a known and a novel pathogenic variant in the ASPM gene in siblings with MCPH5.
• The affected siblings presented with normal intelligence, which is atypical for MCPH5 and suggests a complex genotype-phenotype relationship.
• Further research is needed to elucidate the mechanisms underlying normal intelligence in individuals with these specific ASPM variants and MCPH5.