Clin Genet 2014: 85: 267 – 272 Printed in Singapore. All rights reserved © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12154 Short Report Further genotype–phenotype correlation emerging from two families with PLP1 exon 4 skipping Biancheri R., Grossi S., Regis S., Rossi A., Corsolini F., Rossi D.P., Cavalli P., Severino M., Filocamo M. Further genotype–phenotype correlation emerging from two families with PLP1 exon 4 skipping. Clin Genet 2014: 85: 267–272. © John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2013 Proteolipid protein 1 (PLP1 ) gene-related disorders due to mutations in the PLP1 include a wide spectrum of X-linked disorders ranging from severe connatal Pelizaeus–Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). Duplications, deletions or point mutations in coding and noncoding regions of the PLP1 gene may occur. We report the clinical, neuroradiologic and molecular findings in six patients from two unrelated families. The affected males showed severe mental retardation, spastic tetraparesis, inability of walking and pes cavus at onset in early infancy. Brain magnetic resonance imaging (MRI) showed hypomyelination and brain atrophy. Nystagmus was never observed. The affected females showed adult-onset progressive spastic paraparesis leading to wheel-chair dependency and subtle white matter changes on brain MRI. Molecular studies in the two families identified two different intronic mutations, the novel c.622+2T>C and the known c.622+1G>A, leading to the skipping of PLP1 -exon 4. The clinical presentation of the affected males did not consistently fit in any of the PLP1 -related disorder subtypes (i.e., connatal or classic PMD, SPG2 and ‘PLP1 null syndrome’), and in addition, the carrier females were symptomatic despite the severe clinical picture of their respective probands. This study provides new insight into the genotype–phenotype correlations of patients with PLP1 splice-site mutations. Conflict of interest The authors declare that they have no conflict of interest. Roberta Biancheri a , Serena Grossi b,† , Stefano Regis b,† , Andrea Rossi c , Fabio Corsolini b , Daniela Paola Rossi a , Pietro Cavalli d , Mariasavina Severino c and Mirella Filocamo b a Child Neurology and Psychiatry Unit, b UOSD Centro di diagnostica genetica e biochimica delle malattie metaboliche, c Pediatric Neuroradiology Unit, Istituto G. Gaslini, Genova, Italy, and d Servizio di Genetica, Istituti Ospedalieri di Cremona, Cremona, Italy † These authors equally contributed. Key words: Pelizaeus–Merzbacher disease – magnetic resonance imaging – molecular genetics Corresponding authors: Roberta Biancheri, MD, PhD, Child Neurology and Psychiatry Unit, Istituto G. Gaslini, Largo G. Gaslini 5, 16147 Genova, Italy. Tel.: +39 010 5636432; fax: +39 010 381303; e-mail: roberta@biancheri.com and Mirella Filocamo, BSc, PhD, UOSD, Centro di diagnostica genetica e biochimica delle malattie metaboliche, Istituto G. Gaslini, Largo G. Gaslini 5, 16147 Genova, Italy. Tel.: +39 010 5636792; fax: +39 010 383983; e-mail: mirellafilocamo@ospedale-gaslini.ge.it Received 22 January 2013, revised and accepted for publication 26 March 2013 Proteolipid protein 1 (PLP1 ) gene-related disor- ders include a wide spectrum of X-linked disorders due to mutations in the proteolipid protein gene (PLP1 ; MIM# 300401) ranging from severe connatal Pelizaeus – Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2) (1–3). The gene PLP1 containing seven exons encodes both the 277 amino acid PLP and its 242 amino 267