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A male infant with Xq22.2q22.3 duplication containing PLP1 and MID2.

ABSTRACT: BACKGROUND:The Xq22.2 q23 is a complex genomic region which includes the genes MID2 and PLP1 associated with FG syndrome 5 and Pelizaeus-Merzbacher disease, respectively. There is limited information regarding the clinical outcomes observed in patients with deletions within this region. METHODS:We report on a male infant with intrauterine growth retardation (IUGR) who developed head titubation and spasticity during his postnatal hospital course. RESULTS:Chromosome microarray revealed a 6.7 Mb interstitial duplication of Xq22.2q22.3. Fluorescence in situ hybridization showed that the patient's mother also possessed the identical duplication in the Xq22.3q22.3 region. Among the 34 OMIM genes in this interval, the duplication of the PLP1 (OMIM# 300401) and MID2 (OMIM# 300204) appears to be the most significant contributors to the patient's clinical features. Mutations and duplications of PLP1 are associated with X-linked recessive Pelizaeus-Merzbacher disease (PMD). A single case of a Xq22.3 duplication including the MID2 has been reported in boy with features of FG syndrome. However, our patient's clinical features are not consistent with the FG syndrome phenotype. CONCLUSION:Our patient's clinical features appear to be influenced by the PLP1 duplication but the clinical effect of other dosage sensitive genes influencing brain development cannot be ruled out.

SUBMITTER: Chanchani SR

PROVIDER: S-EPMC7057127 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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A male infant with Xq22.2q22.3 duplication containing PLP1 and MID2.

Chanchani Swati R SR Xie Hongyan H Sekhon Gurbax G Melikishvili Ana M AM Moyer Harasink Sue S Pall Harpreet H Giampietro Philip F PF

Molecular genetics & genomic medicine 20200117 3

<h4>Background</h4>The Xq22.2 q23 is a complex genomic region which includes the genes MID2 and PLP1 associated with FG syndrome 5 and Pelizaeus-Merzbacher disease, respectively. There is limited information regarding the clinical outcomes observed in patients with deletions within this region.<h4>Methods</h4>We report on a male infant with intrauterine growth retardation (IUGR) who developed head titubation and spasticity during his postnatal hospital course.<h4>Results</h4>Chromosome microarra ...[more]

PMID: 31951325

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Project description:The breadth of the clinical spectrum underlying Pelizaeus-Merzbacher disease and spastic paraplegia type 2 is due to the extensive allelic heterogeneity in the X-linked PLP1 gene encoding myelin proteolipid protein (PLP). PLP1 mutations range from gene duplications of variable size found in 60-70% of patients to intragenic lesions present in 15-20% of patients.Forty-eight male patients from 38 unrelated families with a PLP1-related disorder were studied. All DNA samples were screened for PLP1 gene duplications using real-time PCR. PLP1 gene sequencing analysis was performed on patients negative for the duplication. The mutational status of all 14 potential carrier mothers of the familial PLP1 gene mutation was determined as well as 15/24 potential carrier mothers of the PLP1 duplication.PLP1 gene duplications were identified in 24 of the unrelated patients whereas a variety of intragenic PLP1 mutations were found in the remaining 14 patients. Of the 14 different intragenic lesions, 11 were novel; these included one nonsense and 7 missense mutations, a 657-bp deletion, a microdeletion and a microduplication. The functional significance of the novel PLP1 missense mutations, all occurring at evolutionarily conserved residues, was analysed by the MutPred tool whereas their potential effect on splicing was ascertained using the Skippy algorithm and a neural network. Although MutPred predicted that all 7 novel missense mutations would be likely to be deleterious, in silico analysis indicated that four of them (p.Leu146Val, p.Leu159Pro, p.Thr230Ile, p.Ala247Asp) might cause exon skipping by altering exonic splicing elements. These predictions were then investigated in vitro for both p.Leu146Val and p.Thr230Ile by means of RNA or minigene studies and were subsequently confirmed in the case of p.Leu146Val. Peripheral neuropathy was noted in four patients harbouring intragenic mutations that altered RNA processing, but was absent from all PLP1-duplication patients. Unprecedentedly, family studies revealed the de novo occurrence of the PLP1 duplication at a frequency of 20%.

Dataset Information

A male infant with Xq22.2q22.3 duplication containing PLP1 and MID2.

Publications

A male infant with Xq22.2q22.3 duplication containing PLP1 and MID2.

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