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Familial intragenic duplication of ANKRD11 underlying three patients of KBG syndrome.

Crippa M, Rusconi D, Castronovo C, Bestetti I, Russo S, Cereda A, Selicorni A, Larizza L, Finelli P - Mol Cytogenet (2015)

Bottom Line: Here we describe two siblings with multiple symptoms characteristic of KBG and their mother with a milder phenotype.Molecular characterisation of the duplication allele demonstrated the presence of two mutant ANKRD11 transcripts containing a premature stop codon and predicting a truncated non-functional protein.Similarly to deletions and point mutations, this novel pathogenetic rearrangement causes haploinsufficiency of ANKRD11, resulting in KBG syndrome.

View Article: PubMed Central - PubMed

Affiliation: Medical Cytogenetics and Molecular Genetics Lab, IRCCS Istituto Auxologico Italiano, via Ariosto 13, Milano, 20145 Italy.

ABSTRACT

Background: KBG syndrome, a rare autosomal disorder characterised by distinctive craniofacial and skeletal features and developmental delay, is caused by haploinsufficiency of the ANKRD11 gene.

Results: Here we describe two siblings with multiple symptoms characteristic of KBG and their mother with a milder phenotype. In the siblings, array-based comparative genomic hybridization (array CGH) identified an intragenic microduplication affecting ANKRD11 that was absent from the parents' array CGH profiles. Microsatellite analysis revealed the maternal origin of the rearrangement and interphase fluorescent in situ hybridization (i-FISH) experiments identified the rearrangement in low-level mosaicism in the mother. Molecular characterisation of the duplication allele demonstrated the presence of two mutant ANKRD11 transcripts containing a premature stop codon and predicting a truncated non-functional protein.

Conclusions: Similarly to deletions and point mutations, this novel pathogenetic rearrangement causes haploinsufficiency of ANKRD11, resulting in KBG syndrome.

No MeSH data available.


Related in: MedlinePlus

ANKRD11intragenic duplication in the probands and their mother. (a) High-resolution array CGH profiles reveal in both sibs a duplication affecting part of the ANKRD11 coding region. Both parents’ profiles are normal. (b) Physical map of 16q24.3 showing the exon/intron structure of ANKRD11 (dark blue), the BAC probe CTD-3200N1 used in i-FISH (red), the deleted region (blue), and its hypothetical maximum size (dotted line). (c, d) i-FISH of peripheral blood lymphocytes from patient 1 (c) and his mother (d). BAC probe CTD-3200N1 yields two hybridization signals, one of which is enlarged, in all nuclei of patient 1 (c) and in 5% of maternal nuclei (d) (red arrow).
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Fig2: ANKRD11intragenic duplication in the probands and their mother. (a) High-resolution array CGH profiles reveal in both sibs a duplication affecting part of the ANKRD11 coding region. Both parents’ profiles are normal. (b) Physical map of 16q24.3 showing the exon/intron structure of ANKRD11 (dark blue), the BAC probe CTD-3200N1 used in i-FISH (red), the deleted region (blue), and its hypothetical maximum size (dotted line). (c, d) i-FISH of peripheral blood lymphocytes from patient 1 (c) and his mother (d). BAC probe CTD-3200N1 yields two hybridization signals, one of which is enlarged, in all nuclei of patient 1 (c) and in 5% of maternal nuclei (d) (red arrow).

Mentions: Array CGH revealed that both siblings were heterozygous for a novel microduplication of 89 kb in 16q24.3 (chr16:89,350,931–89,439,639, hg19), so far unreported in the Database of Genomic Variants (DGV, http://projects.tcag.ca/variation/project.html) (Figure 2a). The duplication extends from ANKRD11 intron 2 to exon 9 or intron 10, depending on the minimum and maximum size of the duplication inferred from reference transcript NM_013275.5 (Figure 2b). Thus, the proximal breakpoint occurred between oligonucleotides A_16_P03198579 and A_14_P119531, and the distal breakpoint between oligonucleotides A_16_P03198760 and A_16_P20559017 (Figure 2b). Parental molecular karyotypes were normal (Figure 2a).Figure 2


Familial intragenic duplication of ANKRD11 underlying three patients of KBG syndrome.

Crippa M, Rusconi D, Castronovo C, Bestetti I, Russo S, Cereda A, Selicorni A, Larizza L, Finelli P - Mol Cytogenet (2015)

ANKRD11intragenic duplication in the probands and their mother. (a) High-resolution array CGH profiles reveal in both sibs a duplication affecting part of the ANKRD11 coding region. Both parents’ profiles are normal. (b) Physical map of 16q24.3 showing the exon/intron structure of ANKRD11 (dark blue), the BAC probe CTD-3200N1 used in i-FISH (red), the deleted region (blue), and its hypothetical maximum size (dotted line). (c, d) i-FISH of peripheral blood lymphocytes from patient 1 (c) and his mother (d). BAC probe CTD-3200N1 yields two hybridization signals, one of which is enlarged, in all nuclei of patient 1 (c) and in 5% of maternal nuclei (d) (red arrow).
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Related In: Results  -  Collection

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Fig2: ANKRD11intragenic duplication in the probands and their mother. (a) High-resolution array CGH profiles reveal in both sibs a duplication affecting part of the ANKRD11 coding region. Both parents’ profiles are normal. (b) Physical map of 16q24.3 showing the exon/intron structure of ANKRD11 (dark blue), the BAC probe CTD-3200N1 used in i-FISH (red), the deleted region (blue), and its hypothetical maximum size (dotted line). (c, d) i-FISH of peripheral blood lymphocytes from patient 1 (c) and his mother (d). BAC probe CTD-3200N1 yields two hybridization signals, one of which is enlarged, in all nuclei of patient 1 (c) and in 5% of maternal nuclei (d) (red arrow).
Mentions: Array CGH revealed that both siblings were heterozygous for a novel microduplication of 89 kb in 16q24.3 (chr16:89,350,931–89,439,639, hg19), so far unreported in the Database of Genomic Variants (DGV, http://projects.tcag.ca/variation/project.html) (Figure 2a). The duplication extends from ANKRD11 intron 2 to exon 9 or intron 10, depending on the minimum and maximum size of the duplication inferred from reference transcript NM_013275.5 (Figure 2b). Thus, the proximal breakpoint occurred between oligonucleotides A_16_P03198579 and A_14_P119531, and the distal breakpoint between oligonucleotides A_16_P03198760 and A_16_P20559017 (Figure 2b). Parental molecular karyotypes were normal (Figure 2a).Figure 2

Bottom Line: Here we describe two siblings with multiple symptoms characteristic of KBG and their mother with a milder phenotype.Molecular characterisation of the duplication allele demonstrated the presence of two mutant ANKRD11 transcripts containing a premature stop codon and predicting a truncated non-functional protein.Similarly to deletions and point mutations, this novel pathogenetic rearrangement causes haploinsufficiency of ANKRD11, resulting in KBG syndrome.

View Article: PubMed Central - PubMed

Affiliation: Medical Cytogenetics and Molecular Genetics Lab, IRCCS Istituto Auxologico Italiano, via Ariosto 13, Milano, 20145 Italy.

ABSTRACT

Background: KBG syndrome, a rare autosomal disorder characterised by distinctive craniofacial and skeletal features and developmental delay, is caused by haploinsufficiency of the ANKRD11 gene.

Results: Here we describe two siblings with multiple symptoms characteristic of KBG and their mother with a milder phenotype. In the siblings, array-based comparative genomic hybridization (array CGH) identified an intragenic microduplication affecting ANKRD11 that was absent from the parents' array CGH profiles. Microsatellite analysis revealed the maternal origin of the rearrangement and interphase fluorescent in situ hybridization (i-FISH) experiments identified the rearrangement in low-level mosaicism in the mother. Molecular characterisation of the duplication allele demonstrated the presence of two mutant ANKRD11 transcripts containing a premature stop codon and predicting a truncated non-functional protein.

Conclusions: Similarly to deletions and point mutations, this novel pathogenetic rearrangement causes haploinsufficiency of ANKRD11, resulting in KBG syndrome.

No MeSH data available.


Related in: MedlinePlus