Heterozygous inversion on chromosome 17 involving PAFAH1B1 detected by whole genome sequencing in a patient suffering from pachygyria

Lissencephaly (LIS) is a subtype of malformations of cortical development (MCD), characterized by smooth brain surfaces and underdeveloped gyri and sulci. This study investigates the genetic cause of pachygyria in a Chinese male infant diagnosed with the condition, who previously showed no causative variant through trio whole exome sequencing (Trio-WES) and copy number variation sequencing (CNVseq). Whole-genome sequencing (WGS) was conducted, revealing a novel heterozygous inversion spanning 1.02M bps on chromosome 17 [seq[GRCh37]inv(17)(p13.3p13.2)|NC_000017.10:g.2562761_3581978inv] involving the PAFAH1B1 gene. This de novo variant, confirmed by PCR and Sanger sequencing, was present in the proband but absent in the parents. The inversion disrupts PAFAH1B1, classified as haploinsufficient in the ClinGen database, and is associated with lissencephaly-1 (LIS1) and subcortical band heterotopia (SBH) (OMIM #607432). The findings align with the known characteristics of this disorder, extending the understanding of the molecular mechanisms underlying pachygyria. This identification offers new insights for individuals with developmental delays and brain malformations to uncover the genetic cause of their conditions.