Understanding the disease mechanisms and copy number variations at 17p11.2 locus that do not encompass the dosage sensitive RAI1 gene
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
Copy number gains at the 17p11.2 locus involving the dosage sensitive RAI1 gene cause Potocki-Lupski syndrome (PTLS) (MIM: 610883). PTLS is clinically defined by a spectrum of neurodevelopmental phenotypes and congenital anomalies. A diverse set of structural variation mutagenesis mechanisms can cause pathogenic copy number variations at chr17p11.2 locus with the most common being non-allelic homologous recombination (NAHR) between the low copy repeats in two-thirds of individuals with PTLS carrying an ~3.6 Mb recurrent duplication while the remaining one-third carry non-recurrent duplications with a possible replicative repair-based mechanism; both spanning RAI1. When copy number gains are detected surrounding RAI1 but not overlapping with it in individuals with neurodevelopmental phenotypes, they are sometimes clinically diagnosed with PTLS without a molecular cause.
Methods:
We ascertained individuals from 11 families with copy number gains (confirmed by array) at 17p11.2 locus, not spanning RAI1 with a spectrum of neurodevelopmental/neurologic phenotypes. We performed a combination of high-resolution chromosomal microarray (n=11), short-read whole-genome sequencing [WGS, (n=7)], long-read WGS (lr-GS; ONT; n=7 and PacBio HiFi; n=7) and breakpoint junction analysis on this subset to refine complexities and define breakpoints, and understand the possible (or lack of) impact on the driver-RAI1 gene.
Results:
Clinical findings were unavailable for all 11 individuals with 17p11.2 gains excluding RAI1; two of the 11 probands were fetuses. The common features that are shared among this ‘non-RAI1 group’ are delayed language and speech development in 8/9 (89%), gross motor developmental delay in 7/9 (77%), intellectual disability in 5/9 (55%), autism in 5/9 (55%), infantile hypotonia in 4/9 (44%), seizures in 4/9 (44%), sleep apnea in 3/9 (33%), gastroesophageal reflux was found in 3/9 (33%), hearing impairment in 2/9 (22%), and 2/9 (22%) individuals had gait disturbances. The genomic rearrangements identified in this cohort were de novo in 7/11 (64%) families and inherited in 4/11 (36%) including simple duplications (n=7), complex genomic rearrangements [DUP-NML-DUP-NML-DUP (n=1), DEL-DUP (n=1)] and higher order amplifications (a 4X and a 6x amplification, n=2) having same genomic interval, with the distal breakpoint mapping to the polymorphic neoplasia-associated isodicentric 17q cluster, two of which include the Birt-Hogg-Dubé (BHD1; MIM: 135150) locus.
Conclusion:
Individuals with such nonrecurrent genomic variations at chr 17p receive a provisional clinical diagnosis, requiring thorough clinical and multi-genomic evaluation to rule out other disorders with similar non-specific features. The nonrecurrent copy number gains at the 17p11.2 locus excluding the dosage sensitive RAI1 gene also provide an insight upon (i) the mechanisms of structural variant mutagenesis, (ii) mechanisms interfering with RAI1 transcription and function without spanning the gene and (iii) the role of multi-locus pathogenic variations and genes other than the ‘driver RAI1 gene’ as potentially contributing to phenotypes.
Copy number gains at the 17p11.2 locus involving the dosage sensitive RAI1 gene cause Potocki-Lupski syndrome (PTLS) (MIM: 610883). PTLS is clinically defined by a spectrum of neurodevelopmental phenotypes and congenital anomalies. A diverse set of structural variation mutagenesis mechanisms can cause pathogenic copy number variations at chr17p11.2 locus with the most common being non-allelic homologous recombination (NAHR) between the low copy repeats in two-thirds of individuals with PTLS carrying an ~3.6 Mb recurrent duplication while the remaining one-third carry non-recurrent duplications with a possible replicative repair-based mechanism; both spanning RAI1. When copy number gains are detected surrounding RAI1 but not overlapping with it in individuals with neurodevelopmental phenotypes, they are sometimes clinically diagnosed with PTLS without a molecular cause.
Methods:
We ascertained individuals from 11 families with copy number gains (confirmed by array) at 17p11.2 locus, not spanning RAI1 with a spectrum of neurodevelopmental/neurologic phenotypes. We performed a combination of high-resolution chromosomal microarray (n=11), short-read whole-genome sequencing [WGS, (n=7)], long-read WGS (lr-GS; ONT; n=7 and PacBio HiFi; n=7) and breakpoint junction analysis on this subset to refine complexities and define breakpoints, and understand the possible (or lack of) impact on the driver-RAI1 gene.
Results:
Clinical findings were unavailable for all 11 individuals with 17p11.2 gains excluding RAI1; two of the 11 probands were fetuses. The common features that are shared among this ‘non-RAI1 group’ are delayed language and speech development in 8/9 (89%), gross motor developmental delay in 7/9 (77%), intellectual disability in 5/9 (55%), autism in 5/9 (55%), infantile hypotonia in 4/9 (44%), seizures in 4/9 (44%), sleep apnea in 3/9 (33%), gastroesophageal reflux was found in 3/9 (33%), hearing impairment in 2/9 (22%), and 2/9 (22%) individuals had gait disturbances. The genomic rearrangements identified in this cohort were de novo in 7/11 (64%) families and inherited in 4/11 (36%) including simple duplications (n=7), complex genomic rearrangements [DUP-NML-DUP-NML-DUP (n=1), DEL-DUP (n=1)] and higher order amplifications (a 4X and a 6x amplification, n=2) having same genomic interval, with the distal breakpoint mapping to the polymorphic neoplasia-associated isodicentric 17q cluster, two of which include the Birt-Hogg-Dubé (BHD1; MIM: 135150) locus.
Conclusion:
Individuals with such nonrecurrent genomic variations at chr 17p receive a provisional clinical diagnosis, requiring thorough clinical and multi-genomic evaluation to rule out other disorders with similar non-specific features. The nonrecurrent copy number gains at the 17p11.2 locus excluding the dosage sensitive RAI1 gene also provide an insight upon (i) the mechanisms of structural variant mutagenesis, (ii) mechanisms interfering with RAI1 transcription and function without spanning the gene and (iii) the role of multi-locus pathogenic variations and genes other than the ‘driver RAI1 gene’ as potentially contributing to phenotypes.