Postnatal microcephaly and retinal involvement expand the phenotype of RPL10‐related disorder

• Published in: American journal of medical genetics. Part A 2022-10, Vol.188 (10), p.3032-3040
• Main Authors: Cappuccio, Gerarda, De Bernardi, Margherita Lucia, Morlando, Alessia, Peduto, Cristina, Scala, Iris, Pinelli, Michele, Bellacchio, Emanuele, Gallo, Flavio Gioele, Magli, Adriano, Plaitano, Carmen, Serrano, Mercedes, Pías, Leticia, Català, Jaume, Bolasell, Mercè, Torella, Annalaura, Nigro, Vincenzo, Zanni, Ginevra, Brunetti‐Pierri, Nicola
• Format: Article
• Language: English
• Subjects: Autism; Autism Spectrum Disorder; Congenital defects; Epilepsy; Evolutionary conservation; Genotype & phenotype; Genotypes; Humans; Intellectual disabilities; intellectual disability; Intellectual Disability - genetics; Intellectual Disability - pathology; Male; Microcephaly; Microcephaly - genetics; Microcephaly - pathology; Microencephaly; Nervous System Malformations; ocular; Phenotype; Phenotypes; Retina; Retinal degeneration; retinal dystrophy; Retinitis; Retinitis pigmentosa; Retinopathy; RPL10; rRNA 28S
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.62911

Hemizygous missense variants in the RPL10 gene encoding a ribosomal unit are responsible for an X‐linked syndrome presenting with intellectual disability (ID), autism spectrum disorder, epilepsy, dysmorphic features, and multiple congenital anomalies. Among 15 individuals with RPL10‐related disorder reported so far, only one patient had retinitis pigmentosa and microcephaly was observed in approximately half of the cases. By exome sequencing, three Italian and one Spanish male children, from three independent families, were found to carry the same hemizygous novel missense variant p.(Arg32Leu) in RPL10, inherited by their unaffected mother in all cases. The variant, not reported in gnomAD, is located in the 28S rRNA binding region, affecting an evolutionary conserved residue and predicted to disrupt the salt‐bridge between Arg32 and Asp28. In addition to features consistent with RPL10‐related disorder, all four boys had retinal degeneration and postnatal microcephaly. Pathogenic variants in genes responsible for inherited retinal degenerations were ruled out in all the probands. A novel missense RPL10 variant was detected in four probands with a recurrent phenotype including ID, dysmorphic features, progressive postnatal microcephaly, and retinal anomalies. The presented individuals suggest that retinopathy and postnatal microcephaly are clinical clues of RPL10‐related disorder, and at least the retinal defect might be more specific for the p.(Arg32Leu) RPL10 variant, suggesting a specific genotype/phenotype correlation.