Unmasking a Recessive Allele by a Rare Interstitial Deletion at 10q26.13q26.2: Prenatal Diagnosis of MMP21 ‐Related Disorder and Further Refine INSYN2A Involvement in the Postnatal Cognitive Phenotype
ABSTRACT Background The 10q26 microdeletion syndrome (OMIM #609625) is a distinct genomic disorder characterized by a spectrum of clinical features including craniofacial anomalies, developmental delay (DD)/intellectual disability (ID), hypotonia, cardiovascular, and urogenital malformations. Despit...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-02-01
|
| Series: | Molecular Genetics & Genomic Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mgg3.70082 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850238948999168000 |
|---|---|
| author | Jiasun Su Shujie Zhang Wei Li Yuan Wei Fei Lin Chaofan Zhou Xianglian Tang Yueyun Lan Minpan Huang Qiang Zhang Shang Yi Qi Yang Sheng Yi Xunzhao Zhou Zailong Qin Peng Huang |
| author_facet | Jiasun Su Shujie Zhang Wei Li Yuan Wei Fei Lin Chaofan Zhou Xianglian Tang Yueyun Lan Minpan Huang Qiang Zhang Shang Yi Qi Yang Sheng Yi Xunzhao Zhou Zailong Qin Peng Huang |
| author_sort | Jiasun Su |
| collection | DOAJ |
| description | ABSTRACT Background The 10q26 microdeletion syndrome (OMIM #609625) is a distinct genomic disorder characterized by a spectrum of clinical features including craniofacial anomalies, developmental delay (DD)/intellectual disability (ID), hypotonia, cardiovascular, and urogenital malformations. Despite the identification of critical regions within 10q26 linked to the syndrome's phenotype, the specific genes responsible for the associated facial characteristics, microcephaly, cognitive issues, and growth deficiencies remain elusive. Interstitial deletions at 10q25.3‐q26.3 are rare, and their contributions to 10q26 microdeletion syndrome remain unknown. Methods We conducted trio‐whole‐exome sequencing (WES) on a fetus presenting with ventricular septal defect (VSD), aortic span, intrauterine growth retardation (IUGR), and microcephaly. Variant classification was assessed according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, and the causative gene associated with cognitive phenotype was refined by means of smallest regions of overlap (SRO). Results A homozygous variant c.1544A>G (p.Tyr515Cys) in MMP21 and a large deletion at 10q26.13‐q26.2 which unmasked the homozygous mutation were identified in the proband. The maternally inherited 10q26.13q26.2 deletion was classified as likely pathogenic, while the variant c.1544A>G was of uncertain significance (VUS) based on ACMG/AMP criteria. A critical interval of approximately ~500 kb implicating the involving genes DOCK1 and INSYN2A (inhibitory synaptic factor 2A) in the cognitive phenotype of 10q26 microdeletion syndrome was refined. Conclusion This study introduces a recessive MMP21 mutation unmasked by a rare 10q26.13q26.2 deletion via WES in a Chinese fetus with congenital heart disease (CHD), IUGR, and microcephaly. We further refine INSYN2A as a potential candidate gene for cognitive phenotype in 10q26.1‐q26.3 region. Our study also highlights the utility of WES for its advantage in simultaneously analyzing both single nucleotide variants (SNVs) and copy number variants (CNVs) and provide a reference for prenatal diagnosis and genetic counseling in patients with similar conditions. |
| format | Article |
| id | doaj-art-bf8db2048c5746a0a67afe5429584c45 |
| institution | OA Journals |
| issn | 2324-9269 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj-art-bf8db2048c5746a0a67afe5429584c452025-08-20T02:01:19ZengWileyMolecular Genetics & Genomic Medicine2324-92692025-02-01132n/an/a10.1002/mgg3.70082Unmasking a Recessive Allele by a Rare Interstitial Deletion at 10q26.13q26.2: Prenatal Diagnosis of MMP21 ‐Related Disorder and Further Refine INSYN2A Involvement in the Postnatal Cognitive PhenotypeJiasun Su0Shujie Zhang1Wei Li2Yuan Wei3Fei Lin4Chaofan Zhou5Xianglian Tang6Yueyun Lan7Minpan Huang8Qiang Zhang9Shang Yi10Qi Yang11Sheng Yi12Xunzhao Zhou13Zailong Qin14Peng Huang15Genetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaGenetic and Metabolic Central Laboratory of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region Nanning ChinaABSTRACT Background The 10q26 microdeletion syndrome (OMIM #609625) is a distinct genomic disorder characterized by a spectrum of clinical features including craniofacial anomalies, developmental delay (DD)/intellectual disability (ID), hypotonia, cardiovascular, and urogenital malformations. Despite the identification of critical regions within 10q26 linked to the syndrome's phenotype, the specific genes responsible for the associated facial characteristics, microcephaly, cognitive issues, and growth deficiencies remain elusive. Interstitial deletions at 10q25.3‐q26.3 are rare, and their contributions to 10q26 microdeletion syndrome remain unknown. Methods We conducted trio‐whole‐exome sequencing (WES) on a fetus presenting with ventricular septal defect (VSD), aortic span, intrauterine growth retardation (IUGR), and microcephaly. Variant classification was assessed according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, and the causative gene associated with cognitive phenotype was refined by means of smallest regions of overlap (SRO). Results A homozygous variant c.1544A>G (p.Tyr515Cys) in MMP21 and a large deletion at 10q26.13‐q26.2 which unmasked the homozygous mutation were identified in the proband. The maternally inherited 10q26.13q26.2 deletion was classified as likely pathogenic, while the variant c.1544A>G was of uncertain significance (VUS) based on ACMG/AMP criteria. A critical interval of approximately ~500 kb implicating the involving genes DOCK1 and INSYN2A (inhibitory synaptic factor 2A) in the cognitive phenotype of 10q26 microdeletion syndrome was refined. Conclusion This study introduces a recessive MMP21 mutation unmasked by a rare 10q26.13q26.2 deletion via WES in a Chinese fetus with congenital heart disease (CHD), IUGR, and microcephaly. We further refine INSYN2A as a potential candidate gene for cognitive phenotype in 10q26.1‐q26.3 region. Our study also highlights the utility of WES for its advantage in simultaneously analyzing both single nucleotide variants (SNVs) and copy number variants (CNVs) and provide a reference for prenatal diagnosis and genetic counseling in patients with similar conditions.https://doi.org/10.1002/mgg3.7008210q26 microdeletion syndromeinhibitory synaptic factor 2AMMP21unmasking recessive allele |
| spellingShingle | Jiasun Su Shujie Zhang Wei Li Yuan Wei Fei Lin Chaofan Zhou Xianglian Tang Yueyun Lan Minpan Huang Qiang Zhang Shang Yi Qi Yang Sheng Yi Xunzhao Zhou Zailong Qin Peng Huang Unmasking a Recessive Allele by a Rare Interstitial Deletion at 10q26.13q26.2: Prenatal Diagnosis of MMP21 ‐Related Disorder and Further Refine INSYN2A Involvement in the Postnatal Cognitive Phenotype Molecular Genetics & Genomic Medicine 10q26 microdeletion syndrome inhibitory synaptic factor 2A MMP21 unmasking recessive allele |
| title | Unmasking a Recessive Allele by a Rare Interstitial Deletion at 10q26.13q26.2: Prenatal Diagnosis of MMP21 ‐Related Disorder and Further Refine INSYN2A Involvement in the Postnatal Cognitive Phenotype |
| title_full | Unmasking a Recessive Allele by a Rare Interstitial Deletion at 10q26.13q26.2: Prenatal Diagnosis of MMP21 ‐Related Disorder and Further Refine INSYN2A Involvement in the Postnatal Cognitive Phenotype |
| title_fullStr | Unmasking a Recessive Allele by a Rare Interstitial Deletion at 10q26.13q26.2: Prenatal Diagnosis of MMP21 ‐Related Disorder and Further Refine INSYN2A Involvement in the Postnatal Cognitive Phenotype |
| title_full_unstemmed | Unmasking a Recessive Allele by a Rare Interstitial Deletion at 10q26.13q26.2: Prenatal Diagnosis of MMP21 ‐Related Disorder and Further Refine INSYN2A Involvement in the Postnatal Cognitive Phenotype |
| title_short | Unmasking a Recessive Allele by a Rare Interstitial Deletion at 10q26.13q26.2: Prenatal Diagnosis of MMP21 ‐Related Disorder and Further Refine INSYN2A Involvement in the Postnatal Cognitive Phenotype |
| title_sort | unmasking a recessive allele by a rare interstitial deletion at 10q26 13q26 2 prenatal diagnosis of mmp21 related disorder and further refine insyn2a involvement in the postnatal cognitive phenotype |
| topic | 10q26 microdeletion syndrome inhibitory synaptic factor 2A MMP21 unmasking recessive allele |
| url | https://doi.org/10.1002/mgg3.70082 |
| work_keys_str_mv | AT jiasunsu unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype AT shujiezhang unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype AT weili unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype AT yuanwei unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype AT feilin unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype AT chaofanzhou unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype AT xiangliantang unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype AT yueyunlan unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype AT minpanhuang unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype AT qiangzhang unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype AT shangyi unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype AT qiyang unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype AT shengyi unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype AT xunzhaozhou unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype AT zailongqin unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype AT penghuang unmaskingarecessiveallelebyarareinterstitialdeletionat10q2613q262prenataldiagnosisofmmp21relateddisorderandfurtherrefineinsyn2ainvolvementinthepostnatalcognitivephenotype |