Congenital hypogonadotropic hypogonadism (CHH) arises from defects in the synthesis, secretion, or action of gonadotropin-releasing hormone (GnRH), resulting in incomplete or absent pubertal developme Show more
Congenital hypogonadotropic hypogonadism (CHH) arises from defects in the synthesis, secretion, or action of gonadotropin-releasing hormone (GnRH), resulting in incomplete or absent pubertal development and various nonreproductive features. CHH is genetically heterogeneous, with over 50 genes implicated in its pathogenesis. This study aimed to elucidate the genetic variants of CHH in a cohort of patients from a single-center endocrinology unit. We used a targeted next-generation sequencing panel to analyze 52 CHH-related genes in 35 patients. Functional studies validated two of the identified variants. Molecular etiology was identified in 20 of 35 (57%) patients. Among these, 12 (39%) had variants in multiple CHH-related genes, with oligogenic inheritance confirmed in two cases. Novel pathogenic variants (both single nucleotide variants and copy number variants) were identified, including ANOS1 p.Gln238* and c.318+2T>C, CHD7 p.Ser734Ilefs5 and p.Gln592Serfs16, FGFR1 p.Ala36Profs67, c.1663+5G>A, and p.Tyr210*, DMXL2 deletion (83.1 Kb), and SOX2 deletion (1.1 Mb). In total, 21 pathogenic or likely pathogenic variants across 15 CHH-related genes were detected, including ANOS1, CHD7, FGFR1, PROKR2, and others. A functional study confirmed the loss of function in the KISS1R p.Ala203Asp variant. Our findings demonstrate the utility of a next-generation sequencing panel in diagnosing genetically complex conditions like CHH and underscore the role of oligogenic inheritance in its phenotypic diversity. The inclusion of genes previously associated with syndromic CHH forms such as CHARGE in the exome panel may highlight possible shared mechanisms with neurodevelopmental disorders, aiding early diagnosis, genetic counseling, and treatment. Show less
We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (A Show more
We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD. Show less