Genotype-phenotypic correlation in a Chinese patient with isolated lissencephaly sequence caused by 17p13.3p13.2 chromosomal microdeletion: a 6-year follow-up study
TL;DR
The 6-year longitudinal follow-up of ILS in a Chinese patient with severe developmental delay confirmed that haploinsufficiency of the PAFAH1B1 gene was the primary pathogenic cause and expanded the phenotypic spectrum of ILS in Chinese populations.
Abstract
Background Isolated lissencephaly sequence (ILS) is a severe neurodevelopmental disorder associated with 17p13.3 microdeletion. This 6-year longitudinal study aimed to systematically characterize physical and neurodevelopmental trajectories of a Chinese ILS patient and offer evidence for early diagnosis and clinical intervention. Methods From April 2021 to April 2026, a child with severe developmental delay and his family members (parents and elder brother) were recruited in Lianyungang, eastern China. Trio whole-exome sequencing (trio-WES) and copy number variation sequencing (CNV-seq) were used to identify the pathogenic variant. Serial physical growth and neurodevelopmental assessments were conducted during the 6-year longitudinal follow-up. Bioinformatics analysis was used to explore potential molecular pathogenic mechanisms. Results A de novo 2.06 Mb heterozygous deletion at 17p13.3p13.2 (chr17:1707883_3765621del, GRCh37) was identified in the proband, which included PAFAH1B1 but spared YWHAE and CRK. Longitudinal data showed a progressive decline in both height and weight. Height Z score decreased from −0.37 at 2 months to −1.92 at 57 months. Weight Z score decreased from −1.25 at 2 months to −1.79 at 57 months. Gesell developmental quotients (DQ) showed significant progressive declines in five domains with a decelerating trajectory: adaptive behavior (B2 = 0.019, 95% CI: 0.002–0.036, R Q 2 = 0.978), gross motor (B2 = 0.013, 95% CI: -0.004 – 0.030, R Q 2 = 0.944), fine motor (B2 = 0.017, 95% CI: -0.012 – 0.047, R Q 2 = 0.870), language (B2 = 0.021, 95% CI: -0.006 – 0.049, R Q 2 = 0.905), personal social behavior (B2 = 0.020, 95% CI: -0.014 - 0.054, R Q 2 = 0.847). Bioinformatics analysis confirmed that haploinsufficiency of the PAFAH1B1 gene was the primary pathogenic cause. Furthermore, genes in the deleted region were significantly enriched in olfactory perception and calcium ion transmembrane transport pathways. Conclusion This study reports a 6-year longitudinal follow-up of ILS in a Chinese patient. PAFAH1B1 haploinsufficiency causes the core lissencephaly phenotype, while co-deletion of olfactory and calcium-regulatory genes may exert synergistic effects. These findings expand the phenotypic spectrum of ILS in Chinese populations and provide insights for mechanistic studies and genetic counseling.