TY - JOUR
T1 - A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome
AU - Ben-Mahmoud, Afif
AU - Kishikawa, Shotaro
AU - Gupta, Vijay
AU - Leach, Natalia T.
AU - Shen, Yiping
AU - Moldovan, Oana
AU - Goel, Himanshu
AU - Hopper, Bruce
AU - Ranguin, Kara
AU - Gruchy, Nicolas
AU - Maas, Saskia M.
AU - Lacassie, Yves
AU - Kim, Soo-Hyun
AU - Kim, Woo-Yang
AU - Quade, Bradley J.
AU - Morton, Cynthia C.
AU - Kim, Cheol-Hee
AU - Layman, Lawrence C.
AU - Kim, Hyung-Goo
N1 - Funding Information: We thank all the patients and their families for the participation in this study. We are indebted to Robert E. Eisenman for technical assistance and to Amy Bosco for clinical information. We are grateful to the phenotypic assistance from Elise David and Gerard Marion at the Department of Genetics, Reference Center for Rare Diseases of Developmental Anomalies and Polymalformative syndrome, CHU de Caen Normandie, France. We also thank Lynn Chorich and Shahad Sabaawi Ibrahim AlHassan for their assistance in proofreading the final version of the manuscript. Funding Information: This work was supported by an internal grant IGP5 of Qatar Biomedical Research Institute (H.-G.K.), NIH grants GM061354 (Developmental Genome Anatomy Project) and HD28138, and a grant from the National Research Foundation of Korea (2021R1A2C1008506 to C.-H.K). We thankfully acknowledge the support of funding provided by Caroline Jones-Carrick and Collin Carrick. Publisher Copyright: © 2023, Springer Nature Limited.
PY - 2023/12
Y1 - 2023/12
N2 - In a patient diagnosed with both Kallmann syndrome (KS) and intellectual disability (ID), who carried an apparently balanced translocation t(7;12)(q22;q24)dn, array comparative genomic hybridization (aCGH) disclosed a cryptic heterozygous 4.7 Mb deletion del(12)(p11.21p11.23), unrelated to the translocation breakpoint. This novel discovery prompted us to consider the possibility that the combination of KS and neurological disorder in this patient could be attributed to gene(s) within this specific deletion at 12p11.21-12p11.23, rather than disrupted or dysregulated genes at the translocation breakpoints. To further support this hypothesis, we expanded our study by screening five candidate genes at both breakpoints of the chromosomal translocation in a cohort of 48 KS patients. However, no mutations were found, thus reinforcing our supposition. In order to delve deeper into the characterization of the 12p11.21-12p11.23 region, we enlisted six additional patients with small copy number variations (CNVs) and analyzed eight individuals carrying small CNVs in this region from the DECIPHER database. Our investigation utilized a combination of complementary approaches. Firstly, we conducted a comprehensive phenotypic-genotypic comparison of reported CNV cases. Additionally, we reviewed knockout animal models that exhibit phenotypic similarities to human conditions. Moreover, we analyzed reported variants in candidate genes and explored their association with corresponding phenotypes. Lastly, we examined the interacting genes associated with these phenotypes to gain further insights. As a result, we identified a dozen candidate genes: TSPAN11 as a potential KS candidate gene, TM7SF3, STK38L, ARNTL2, ERGIC2, TMTC1, DENND5B, and ETFBKMT as candidate genes for the neurodevelopmental disorder, and INTS13, REP15, PPFIBP1, and FAR2 as candidate genes for KS with ID. Notably, the high-level expression pattern of these genes in relevant human tissues further supported their candidacy. Based on our findings, we propose that dosage alterations of these candidate genes may contribute to sexual and/or cognitive impairments observed in patients with KS and/or ID. However, the confirmation of their causal roles necessitates further identification of point mutations in these candidate genes through next-generation sequencing.
AB - In a patient diagnosed with both Kallmann syndrome (KS) and intellectual disability (ID), who carried an apparently balanced translocation t(7;12)(q22;q24)dn, array comparative genomic hybridization (aCGH) disclosed a cryptic heterozygous 4.7 Mb deletion del(12)(p11.21p11.23), unrelated to the translocation breakpoint. This novel discovery prompted us to consider the possibility that the combination of KS and neurological disorder in this patient could be attributed to gene(s) within this specific deletion at 12p11.21-12p11.23, rather than disrupted or dysregulated genes at the translocation breakpoints. To further support this hypothesis, we expanded our study by screening five candidate genes at both breakpoints of the chromosomal translocation in a cohort of 48 KS patients. However, no mutations were found, thus reinforcing our supposition. In order to delve deeper into the characterization of the 12p11.21-12p11.23 region, we enlisted six additional patients with small copy number variations (CNVs) and analyzed eight individuals carrying small CNVs in this region from the DECIPHER database. Our investigation utilized a combination of complementary approaches. Firstly, we conducted a comprehensive phenotypic-genotypic comparison of reported CNV cases. Additionally, we reviewed knockout animal models that exhibit phenotypic similarities to human conditions. Moreover, we analyzed reported variants in candidate genes and explored their association with corresponding phenotypes. Lastly, we examined the interacting genes associated with these phenotypes to gain further insights. As a result, we identified a dozen candidate genes: TSPAN11 as a potential KS candidate gene, TM7SF3, STK38L, ARNTL2, ERGIC2, TMTC1, DENND5B, and ETFBKMT as candidate genes for the neurodevelopmental disorder, and INTS13, REP15, PPFIBP1, and FAR2 as candidate genes for KS with ID. Notably, the high-level expression pattern of these genes in relevant human tissues further supported their candidacy. Based on our findings, we propose that dosage alterations of these candidate genes may contribute to sexual and/or cognitive impairments observed in patients with KS and/or ID. However, the confirmation of their causal roles necessitates further identification of point mutations in these candidate genes through next-generation sequencing.
UR - http://www.scopus.com/inward/record.url?scp=85167671337&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41598-023-40037-4
DO - https://doi.org/10.1038/s41598-023-40037-4
M3 - Article
C2 - 37563198
SN - 2045-2322
VL - 13
SP - 12984
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 12984
ER -