A 25 Mainland Chinese cohort of patients with PURA-related neurodevelopmental disorders: clinical delineation and genotype-phenotype correlations

PURA-related neurodevelopmental disorders (PURA-NDDs) include 5q31.3 microdeletion syndrome and PURA syndrome. PURA has been proposed as a candidate gene responsible for 5q31.3 microdeletion syndrome. Phenotype comparisons between patients with PURA mutations and 5q31.3 microdeletions encompassing more than PURA gene are lacking. A total of 25 previously undescribed Mainland China patients were evaluated. Clinical data were obtained from medical record review and standardized medical history questionnaire. Clinical profile and genetic spectrum of the patients with PURA syndrome and genotype-phenotype correlations between PURA mutations group and 5q31.3 microdeletions group were analyzed. Our identified seventeen de nove PURA variants were novel, and two recurrent frameshift variants, c.697_699del (p.F233del) and c.159dup (p.L54Afs*147) were detected in the four independent pedigrees. One patient with 5q31.3 microdeletion further supported the shortest overlapping region only contains PURA and IGIP gene. Developmental delay/intellectual disability, neonatal hypotonia, neonatal feeding difficulties, hypersomnolence and dysmorphic features were prominent clinical features in PURA syndrome. There was no significant difference between two groups in incidence of neonatal problems, developmental delay and common medical comorbidities. We observed a higher frequency of abnormal brain MRI and specific facial dysmorphism in 5q31.3 microdeletion group. This is the first work describing a largest cohort of Mainland China patients broaden the clinical and molecular spectrum of PURA-NDDs. Our findings not only demonstrated that PURA haploinsufficiency was a major contributor to the important phenotypes of 5q31.3 microdeletion, but also implied that additional genes still played a role in the 5q31.3 microdeletion.