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De novo microduplication of CHL1 in a patient with non-syndromic developmental phenotypes.

Palumbo O, Fischetto R, Palumbo P, Nicastro F, Papadia F, Zelante L, Carella M - Mol Cytogenet (2015)

Bottom Line: Less is known about the potential effect of CHL1 overexpression, and microduplications of CHL1 have been rarely identified.To the best of our knowledge, duplication of chromosome 3p26.3, including only the CHL1 gene, has been described in only one intellectually disabled girl with epilepsy.The clinical and molecular findings reported here are useful to provide further evidence that CHL1 is a dosage sensitive gene suggesting that not only the deletion but also its duplication can cause non-syndromic neurodevelopmental phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio di Genetica Medica, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, (FG) Italy.

ABSTRACT

Background: The CHL1 gene codes for a member of the L1 family of neural cell adhesion molecules. It is highly expressed in the central and peripheral nervous system playing an important role in the building and functioning on the brain. CHL1 proteins are also involved in axonal migration, synaptic formation and plasticity. In mice, functional studies showed that the haploinsufficiency of Chl1 gene in the developing brain results in cognitive deficits suggesting that the CHL1 gene at 3p26.3 is a candidate for an autosomal form of intellectual disability. Furthermore, in humans deletions of CHL1 have been described in patients with neurodevelopmental delay characterized by learning and language difficulties, seizures. Less is known about the potential effect of CHL1 overexpression, and microduplications of CHL1 have been rarely identified.

Case presentation: In this report, we describe a male patient with a phenotype characterized by developmental delay, symptoms of hyperactivity, short attention span and speech delay. In addition, minor facial dysmorphic features have been observed. Chromosomal microarray analysis revealed a rare de novo 0.85 Mb microduplication on the short arm (p26.3) of chromosome 3, encompassing a single gene, CHL1. To the best of our knowledge, duplication of chromosome 3p26.3, including only the CHL1 gene, has been described in only one intellectually disabled girl with epilepsy. The duplication described here is the smallest reported so far. In addition, this is the first report describing a patient in which the CHL1 duplication is a de novo event.

Conclusions: The clinical and molecular findings reported here are useful to provide further evidence that CHL1 is a dosage sensitive gene suggesting that not only the deletion but also its duplication can cause non-syndromic neurodevelopmental phenotypes.

No MeSH data available.


Related in: MedlinePlus

Snapshot of the 3p26.3 region displayed using the UCSC Genome browser [GRCh37/hg19 assembly; http://genome.ucsc.edu] showing the CHL1 duplications seen in the present patient and in the first patient reported in the literature
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Fig3: Snapshot of the 3p26.3 region displayed using the UCSC Genome browser [GRCh37/hg19 assembly; http://genome.ucsc.edu] showing the CHL1 duplications seen in the present patient and in the first patient reported in the literature

Mentions: Until now, only another patient carrier of a CNV similar for size and chromosomal location to that identified in our patient, has been reported in medical literature by Shoukier et al. [6]. The clinical manifestations of the present case along with the patient reported by Shoukier et al. are listed in Table 1 while the molecular data of the two patients are presented in Fig. 3. A review of clinical features in these two patients revealed overlapping phenotypes, namely, ID/DD and speech delay. Since CHL1 has important regulatory functions both in developing brain and in mature neurons [1–3], we conclude that CHL1 duplication is likely responsible for the patient’s phenotype. Our observation is also corroborated by the fact that the duplication reported in the present case is the first described to date as de novo event in a patient with non-syndromic developmental delay. In addition, copy number variations of genes encoding for neural cell adhesion molecules (NCAM), have been recently published in the literature as responsible for neurodevelopmental disorders further strengthening the hypothesis that chromosomal alteration affecting this family of genes can cause neurodevelopmental disorders [12].Table 1


De novo microduplication of CHL1 in a patient with non-syndromic developmental phenotypes.

Palumbo O, Fischetto R, Palumbo P, Nicastro F, Papadia F, Zelante L, Carella M - Mol Cytogenet (2015)

Snapshot of the 3p26.3 region displayed using the UCSC Genome browser [GRCh37/hg19 assembly; http://genome.ucsc.edu] showing the CHL1 duplications seen in the present patient and in the first patient reported in the literature
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4537544&req=5

Fig3: Snapshot of the 3p26.3 region displayed using the UCSC Genome browser [GRCh37/hg19 assembly; http://genome.ucsc.edu] showing the CHL1 duplications seen in the present patient and in the first patient reported in the literature
Mentions: Until now, only another patient carrier of a CNV similar for size and chromosomal location to that identified in our patient, has been reported in medical literature by Shoukier et al. [6]. The clinical manifestations of the present case along with the patient reported by Shoukier et al. are listed in Table 1 while the molecular data of the two patients are presented in Fig. 3. A review of clinical features in these two patients revealed overlapping phenotypes, namely, ID/DD and speech delay. Since CHL1 has important regulatory functions both in developing brain and in mature neurons [1–3], we conclude that CHL1 duplication is likely responsible for the patient’s phenotype. Our observation is also corroborated by the fact that the duplication reported in the present case is the first described to date as de novo event in a patient with non-syndromic developmental delay. In addition, copy number variations of genes encoding for neural cell adhesion molecules (NCAM), have been recently published in the literature as responsible for neurodevelopmental disorders further strengthening the hypothesis that chromosomal alteration affecting this family of genes can cause neurodevelopmental disorders [12].Table 1

Bottom Line: Less is known about the potential effect of CHL1 overexpression, and microduplications of CHL1 have been rarely identified.To the best of our knowledge, duplication of chromosome 3p26.3, including only the CHL1 gene, has been described in only one intellectually disabled girl with epilepsy.The clinical and molecular findings reported here are useful to provide further evidence that CHL1 is a dosage sensitive gene suggesting that not only the deletion but also its duplication can cause non-syndromic neurodevelopmental phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio di Genetica Medica, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, (FG) Italy.

ABSTRACT

Background: The CHL1 gene codes for a member of the L1 family of neural cell adhesion molecules. It is highly expressed in the central and peripheral nervous system playing an important role in the building and functioning on the brain. CHL1 proteins are also involved in axonal migration, synaptic formation and plasticity. In mice, functional studies showed that the haploinsufficiency of Chl1 gene in the developing brain results in cognitive deficits suggesting that the CHL1 gene at 3p26.3 is a candidate for an autosomal form of intellectual disability. Furthermore, in humans deletions of CHL1 have been described in patients with neurodevelopmental delay characterized by learning and language difficulties, seizures. Less is known about the potential effect of CHL1 overexpression, and microduplications of CHL1 have been rarely identified.

Case presentation: In this report, we describe a male patient with a phenotype characterized by developmental delay, symptoms of hyperactivity, short attention span and speech delay. In addition, minor facial dysmorphic features have been observed. Chromosomal microarray analysis revealed a rare de novo 0.85 Mb microduplication on the short arm (p26.3) of chromosome 3, encompassing a single gene, CHL1. To the best of our knowledge, duplication of chromosome 3p26.3, including only the CHL1 gene, has been described in only one intellectually disabled girl with epilepsy. The duplication described here is the smallest reported so far. In addition, this is the first report describing a patient in which the CHL1 duplication is a de novo event.

Conclusions: The clinical and molecular findings reported here are useful to provide further evidence that CHL1 is a dosage sensitive gene suggesting that not only the deletion but also its duplication can cause non-syndromic neurodevelopmental phenotypes.

No MeSH data available.


Related in: MedlinePlus