Recurrent 2q11.2 deletions and duplications: A look at segregation, clinical presentation, and additional genetic testing
Laboratory Genetics and Genomics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction:
Recurrent copy number variants (rCNVs) are deletions or duplications mediated by segmental duplications resulting in recurrent breakpoints. rCNVs involving 2q11.2 are approximately ~1.0-1.5Mb in size and encompass more than 15 protein-coding RefSeq genes including ARID5A, TMEM127, and LMAN2L. 2q11.2 deletions have been previously reported in at least 6 individuals from 5 unrelated families with variable features including speech delay, ADHD, and dysmorphic features; 2q11.2 duplications have been reported in 4 individuals from 3 unrelated families with developmental delay, dysmorphic features, gastroesophageal reflux (GERD), and short stature [PMID: 26227573; PMID: 19443486]. Additionally, 2q11.2 deletions were observed in 31 individuals (0.007%) from the UK biobank (reported to have no neurodevelopmental disorder) with an estimated penetrance of 13% [PMID: 30767844].
Due to the small number of individuals that have been reported with rCNVs affecting 2q11.2, the objective of this study was to characterize 2q11.2 rCNVs observed at the Genomic Diagnostic Laboratory (GDL) at the Children’s Hospital of Philadelphia (CHOP). To date, more than 20,000 individuals have had whole genome copy number analysis via SNP Microarray, whole exome/genome sequencing, or targeted panel testing on a genome platform. This study aimed at reviewing segregation data, clinical presentation, and additional genetic testing performed in individuals identified in our laboratory with 2q11.2 rCNVs.
Methods:
A retrospective study of all individuals with whole genome copy number variant testing (SNP microarray, exome/genome sequencing, or targeted panel testing) performed in the GDL at CHOP was completed to identify families with 2q11.2 rCNVs. A detailed review of the medical record for these families was performed to assess relevant clinical, developmental, and family histories and review additional genetic testing results.
Results:
2q11.2 deletions were identified in four probands; 3/4 (75%) are reported to have neurodevelopmental phenotypes, 2/4 (50%) have sensorineural hearing loss (with a third individual reported to have hearing aids for an auditory processing disorder), 1/4 (25%) has microcephaly, and 4/4 (100%) are characterized as obese. Parental testing was performed in two families and revealed inheritance from two unaffected parents. No TMEM127-associated cancers were reported in this cohort. Additional targeted panel sequencing was performed in three probands, with inconclusive or negative results. Sequence variants were reported in at least two probands including one individual with a pathogenic MT-TS1 variant identified at 13% heteroplasmy with unclear clinical significance.
2q11.2 duplications were identified in four probands; 4/4 (100%) are reported to have neurodevelopmental phenotypes, 2 are reported to have GERD, and 3 are reported to have growth abnormalities (failure to thrive, IUGR, small head circumference). Parental testing was performed in two families and this rCNV was inherited from an unaffected parent in one family and was not inherited from the mother in the second family (however, the father was unavailable for analysis). Additionally, this variant was identified incidentally in an apparently unaffected individual who was undergoing parental testing for an unrelated CNV found in her affected child who did not harbor the 2q11.2 duplication. Additional targeted panel and/or whole exome sequencing was performed in three of the probands. One proband has a likely pathogenic KCNQ2 variant and an additional proband has a paternally inherited likely pathogenic WFS1 variant.
Conclusion:
Current classification guidelines are intended for highly penetrant Mendelian disorders. Due to the segregation data and inconsistent clinical presentations, there does not appear to be clear evidence that 2q11.2 rCNVs are associated with highly penetrant phenotypes. However, we cannot rule out the possibility these CNVs are risk factors for various neurodevelopmental phenotypes. Further studies are needed to investigate the clinical significance of rCNVs impacting 2q11.2.
Recurrent copy number variants (rCNVs) are deletions or duplications mediated by segmental duplications resulting in recurrent breakpoints. rCNVs involving 2q11.2 are approximately ~1.0-1.5Mb in size and encompass more than 15 protein-coding RefSeq genes including ARID5A, TMEM127, and LMAN2L. 2q11.2 deletions have been previously reported in at least 6 individuals from 5 unrelated families with variable features including speech delay, ADHD, and dysmorphic features; 2q11.2 duplications have been reported in 4 individuals from 3 unrelated families with developmental delay, dysmorphic features, gastroesophageal reflux (GERD), and short stature [PMID: 26227573; PMID: 19443486]. Additionally, 2q11.2 deletions were observed in 31 individuals (0.007%) from the UK biobank (reported to have no neurodevelopmental disorder) with an estimated penetrance of 13% [PMID: 30767844].
Due to the small number of individuals that have been reported with rCNVs affecting 2q11.2, the objective of this study was to characterize 2q11.2 rCNVs observed at the Genomic Diagnostic Laboratory (GDL) at the Children’s Hospital of Philadelphia (CHOP). To date, more than 20,000 individuals have had whole genome copy number analysis via SNP Microarray, whole exome/genome sequencing, or targeted panel testing on a genome platform. This study aimed at reviewing segregation data, clinical presentation, and additional genetic testing performed in individuals identified in our laboratory with 2q11.2 rCNVs.
Methods:
A retrospective study of all individuals with whole genome copy number variant testing (SNP microarray, exome/genome sequencing, or targeted panel testing) performed in the GDL at CHOP was completed to identify families with 2q11.2 rCNVs. A detailed review of the medical record for these families was performed to assess relevant clinical, developmental, and family histories and review additional genetic testing results.
Results:
2q11.2 deletions were identified in four probands; 3/4 (75%) are reported to have neurodevelopmental phenotypes, 2/4 (50%) have sensorineural hearing loss (with a third individual reported to have hearing aids for an auditory processing disorder), 1/4 (25%) has microcephaly, and 4/4 (100%) are characterized as obese. Parental testing was performed in two families and revealed inheritance from two unaffected parents. No TMEM127-associated cancers were reported in this cohort. Additional targeted panel sequencing was performed in three probands, with inconclusive or negative results. Sequence variants were reported in at least two probands including one individual with a pathogenic MT-TS1 variant identified at 13% heteroplasmy with unclear clinical significance.
2q11.2 duplications were identified in four probands; 4/4 (100%) are reported to have neurodevelopmental phenotypes, 2 are reported to have GERD, and 3 are reported to have growth abnormalities (failure to thrive, IUGR, small head circumference). Parental testing was performed in two families and this rCNV was inherited from an unaffected parent in one family and was not inherited from the mother in the second family (however, the father was unavailable for analysis). Additionally, this variant was identified incidentally in an apparently unaffected individual who was undergoing parental testing for an unrelated CNV found in her affected child who did not harbor the 2q11.2 duplication. Additional targeted panel and/or whole exome sequencing was performed in three of the probands. One proband has a likely pathogenic KCNQ2 variant and an additional proband has a paternally inherited likely pathogenic WFS1 variant.
Conclusion:
Current classification guidelines are intended for highly penetrant Mendelian disorders. Due to the segregation data and inconsistent clinical presentations, there does not appear to be clear evidence that 2q11.2 rCNVs are associated with highly penetrant phenotypes. However, we cannot rule out the possibility these CNVs are risk factors for various neurodevelopmental phenotypes. Further studies are needed to investigate the clinical significance of rCNVs impacting 2q11.2.