What question did this study set out to answer?

To investigate the connection between GNAS deletions, imprinting disturbances, and severe infantile obesity.

March 31, 2026Open Access

Severe infantile obesity with a maternal GNAS deletion and multi-locus imprinting disturbance including hypomethylation of the KCNQ1OT1:TSS-DMR

TUTatsuki UrakawaNational Center For Child Health and Development MSMasaharu ShimadaGunma University SSShinichiro SanoHamamatsu University School of Medicine

Key Points

To investigate the connection between GNAS deletions, imprinting disturbances, and severe infantile obesity.
Genome-wide copy number variation analysis
Genome-wide methylation analysis
Whole-exome sequencing
Assessment of body mass index (BMI)
Genetic screening of the patient's parents
Patient exhibited severe infantile obesity with BMI greater than 33 kg/m2
Identification of GNAS deletion on maternal allele
Hypomethylation found in KCNQ1OT1:TSS-DMR
Patient had PTH resistance consistent with PHP1A
Mother carried a benign ZAR1 missense variant

Abstract

Genetic defects in GNAS on the maternal allele cause pseudohypoparathyroidism type 1A (PHP1A) with PTH resistance. Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome caused by aberrant methylation in the KCNQ1OT1:transcription start site (TSS)-differentially methylated region (DMR). PHP1A and BWS exhibit postnatal overgrowth. Recently, multi-locus imprinting disturbance (MLID) has been observed in cases with BWS. Deleterious variants in genes encoding proteins that maintain CpG methylation at DMRs have been found in MLID cases and/or their mothers, and ZAR1 is supposed to be one of the MLID causative genes. In this study, we identified a patient with a deletion involving Gsα-coding region and MLID including hypomethylation of the KCNQ1OT1:TSS-DMR by genome-wide copy number variation analysis, genome-wide methylation analysis, and whole-exome sequencing. The patient’s mother had a deletion of the same region on the paternal allele and carried a ZAR1 missense variant considered benign. The patient exhibited severe infantile obesity with a body mass index greater than 33 kg/m2 and PTH resistance due to the comorbidity of PHP1A and MLID including hypomethylation of the KCNQ1OT1:TSS-DMR. This study highlights the importance of screening for PHP1A and imprinting disorders with overgrowth, in cases with severe infantile obesity, and for MLID causative genes in MLID cases.

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