Optic genome mapping reveals a complex chromosome rearrangement disrupting SYT1 in an individual with a neurodevelopmental disorder
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
Baker-Gordon syndrome (BAGOS) is an autosomal dominant neurodevelopmental disorder characterized by hypotonia/developmental delay/intellectual disability, with severe speech compromise, behavioral and EEG abnormalies, hyperkinetic movements, mild dysmorphic facial features, ophthalmologic and skeletal anomalies. This disorder is caused by de novo heterozygous, missense mutations in the SYT1, which codes for a membrane protein that plays a role in vesicular trafficking and exocytosis. The precise pathogenic mechanism of BAGOS syndrome is still unclear, with preliminary data favoring a dominant-negative effect. Nonetheless, a recent case was reported presenting a reciprocal translocation between chromosomes 7 and 12, with one of the breakpoints mapped in the second intron of SYT1, supporting haploinsufficiency as the molecular mechanism responsible for the neurodevelopmental issues in the patient. Optic genome mapping (OGM) is a novel technique using ultra high molecular weight DNA molecules allowing the combined analyses of numerical and structural chromosome variants
Methods:
We report a 12-year-old girl, the only child of non-consanguineous, young parents presenting developmental delay with severe speech compromise, intellectual disability, autism, seizures, behavioral abnormality with hetero/auto-aggression; short stature; dysmorphic facial features; hirsutism, vesicoureteral reflux. Cranial MRI and fundoscopy were normal. Previous genetic investigation included: an apparently balanced translocation [46,XX,t(5:12)(q31q31;q21)], with no pathogenic variants in chromosomal microarray analysis, and a heterozygous pathogenic missense variant in IVD, identified by exome sequencing, with no detection of increased excretion of organic acids in urine. Karyotype in the mother was normal and father was not available for evaluation. To further characterize the apparent balanced translocation, OGM was applied.
Results:
OGM analysis revealed a more complex chromosomal rearrangement, confirming the translocation t(5;12) and revealing a previously not detected paracentric inversion in the long arm of chromosome 12: ogm[GRCh38] (X,1–22)×2, t(5;12)(q21.3;q14.2)(107673586;63775716) and ogm[GRCh38] (X,1–22)×2, inv(12)(q14.2q21.1)(63786531_79358882). Analyzing the breakpoints of the 12q paracentric inversion, one of them is located in intron 9 of SYT1.
Conclusion:
This case report highlights the effectiveness of OGM technology in identifying complex structural variants. Moreover, this is the second individual reported in the literature presenting BAGOS caused by SYT1 disruption, supporting haploinsufficiency as the pathogenic mechanism for this condition.
Baker-Gordon syndrome (BAGOS) is an autosomal dominant neurodevelopmental disorder characterized by hypotonia/developmental delay/intellectual disability, with severe speech compromise, behavioral and EEG abnormalies, hyperkinetic movements, mild dysmorphic facial features, ophthalmologic and skeletal anomalies. This disorder is caused by de novo heterozygous, missense mutations in the SYT1, which codes for a membrane protein that plays a role in vesicular trafficking and exocytosis. The precise pathogenic mechanism of BAGOS syndrome is still unclear, with preliminary data favoring a dominant-negative effect. Nonetheless, a recent case was reported presenting a reciprocal translocation between chromosomes 7 and 12, with one of the breakpoints mapped in the second intron of SYT1, supporting haploinsufficiency as the molecular mechanism responsible for the neurodevelopmental issues in the patient. Optic genome mapping (OGM) is a novel technique using ultra high molecular weight DNA molecules allowing the combined analyses of numerical and structural chromosome variants
Methods:
We report a 12-year-old girl, the only child of non-consanguineous, young parents presenting developmental delay with severe speech compromise, intellectual disability, autism, seizures, behavioral abnormality with hetero/auto-aggression; short stature; dysmorphic facial features; hirsutism, vesicoureteral reflux. Cranial MRI and fundoscopy were normal. Previous genetic investigation included: an apparently balanced translocation [46,XX,t(5:12)(q31q31;q21)], with no pathogenic variants in chromosomal microarray analysis, and a heterozygous pathogenic missense variant in IVD, identified by exome sequencing, with no detection of increased excretion of organic acids in urine. Karyotype in the mother was normal and father was not available for evaluation. To further characterize the apparent balanced translocation, OGM was applied.
Results:
OGM analysis revealed a more complex chromosomal rearrangement, confirming the translocation t(5;12) and revealing a previously not detected paracentric inversion in the long arm of chromosome 12: ogm[GRCh38] (X,1–22)×2, t(5;12)(q21.3;q14.2)(107673586;63775716) and ogm[GRCh38] (X,1–22)×2, inv(12)(q14.2q21.1)(63786531_79358882). Analyzing the breakpoints of the 12q paracentric inversion, one of them is located in intron 9 of SYT1.
Conclusion:
This case report highlights the effectiveness of OGM technology in identifying complex structural variants. Moreover, this is the second individual reported in the literature presenting BAGOS caused by SYT1 disruption, supporting haploinsufficiency as the pathogenic mechanism for this condition.