Mild ring 17 syndrome shares common phenotypic features irrespective of the chromosomal breakpoints location

Abstract

Ring 17 syndrome is a rare disorder with clinical features influenced by the presence or deletion of the Miller-Dieker critical region (MDCR). Presence of the MDCR is associated with a mild phenotype, including growth delay (GD), mental retardation (MR), seizures, cafè au lait skin (CALS) spots and minor facial dysmorphisms. Previous studies have been mainly focused on this locus providing poor information about the role of other genes located on the p- and q-arms. Here, we used bacterial artificial chromosome (BAC)/P1 artificial chromosome (PAC) and fosmid clones as fluorescence in situ hybridization (FISH) probes to perform a cyto-molecular analysis of a ring 17 case and found that the breakpoints were close to the telomeric ends. METRNL is the sole gene located on the q-arm terminal end, whereas two open reading frames and the RPH3AL gene are located on the terminal p-arm. To detect possibly unrevealed small deletions involving the transcription units, we used subcloned FISH probes obtained by long-range polymerase chain reaction (PCR), which showed that the investigated regions were preserved. Comparing our findings with other reports, it emerges that different breakpoints, involving (or not) large genomic deletions, present overlapping clinical aspects. In conclusion, our data suggest that a mechanism based on gene expression control besides haploinsufficiency should be considered to explain the common phenotypic features found in the mild ring 17 syndrome.

Ring Chromosome 17 Not Involving the Miller-Dieker Region: A Case with Drug-Resistant Epilepsy

“…A previous review of all ring chromosome 17 cases, without MDCR involvement, showed shared common phenotypic features with no consistency in copy number losses [Charles et al, 1991;Surace et al, 2009]. This observation is supported by our case which, in comparison to the only 2 other cases with a detailed description of epilepsy, showed a discrepant copy number loss [RicardMousnier et al, 2007;de Palma et al, 2015].…”

“…Ring chromosome 17 without MDCR involvement is rare [Qazi et al, 1979;Chudley et al, 1982;Charles et al, 1991;Gass and Taney, 1994;Endo et al, 1999;Shashi et al, 2003;Ricard-Mousnier et al, 2007;Kumari et al, 2009;Surace et al, 2009;de Palma et al, 2015]. Epilepsy, although reported in all cases, is well described in only 2 patients, both presenting with nocturnal focal seizures and prolonged diurnal nonconvulsive status epilepticus [Ricard-Mousnier et al, 2007;de Palma et al, 2015].…”

“…Epilepsy has also been reported, but a definite phenotype has not been described [Shimojima et al, 2010]. If MDCR is not involved in ring 17 formation, the phenotype is milder and may include growth delay, intellectual disability, seizures, café-aulait skin lesions, minor dysmorphism, and a flecked retina [Charles et al, 1991;Shashi et al, 2003;Surace et al, 2009].…”

Latent process genes for cell differentiation are common decoders of neurite extension length

“…Several early studies of relevant proteins suggest their potential roles, but a role for Metrnl has not yet been reported. However, the Nterminus of METRNL shows homology with that of meteorin, a secreted protein that is involved in the development of the nervous system and in glial cell differentiation and axonal extension (Nishino et al, 2004;Surace et al, 2009). METRNL might be involved in neurite extension as a secreted protein in a similar manner.…”

Clinical Reasoning: A girl presenting with stiffness episodes during sleep, café-au-lait spots, and flecked retina

“…1 Ring chromosome 17 is a rare genetic abnormality described, to date, in 17 patients. 2 Seizures, mental retardation, skin manifestations, and reduced growth are very common in affected subjects. However, the clinical phenotype is highly variable, and this can be in relation to the deletion size.…”