CRELD1-Associated Neurodevelopmental Disorder: Three New Individuals from Unrelated Families

<b>Background:</b><i>CRELD1</i> encodes a cell adhesion molecule initially implicated in atrioventricular septal defects (AVSDs). More recently, biallelic <i>CRELD1</i> variants have been associated with syndromic and non-syndromic neurodevelopmental disorders (NDDs). <b>Methods:</b> We describe three individuals from unrelated families with compound heterozygous <i>CRELD1</i> variants, identified through exome sequencing. Clinical and genetic data were reviewed to delineate shared and divergent features. <b>Results:</b> All three patients presented with developmental delay, intellectual disability, seizures, hypotonia, and dysmorphic facial features. Patient 1 and patient 2 carried a recurrent variant combination previously reported in five individuals, while Patient 3 harboured the recurrent frameshift p.(Gln320Argfs*25) variant in trans with a novel missense variant. The milder clinical course of patient 3 highlights phenotypic heterogeneity. Notably, none of the patients had cardiac anomalies or immunological abnormalities, further expanding the clinical spectrum associated with <i>CRELD1</i>. <b>Conclusion:</b> Our findings reinforce genotype-phenotype correlations and provide additional evidence that biallelic <i>CRELD1</i> variants underlie a distinct autosomal recessive neurodevelopmental disorder, broadening both the phenotypic and genetic spectrum of this emerging syndrome.