GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

Abstract

Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare, related diseases that prevent normal pubertal development and cause infertility in affected men and women.However, the infertility carries a good prognosis as increasing numbers of patients with CHH/KS are now able to have children through medically assisted procreation.These are genetic diseases that can be transmitted to patients' offspring. Importantly patients and their families should be informed of this risk and given genetic counseling. CHH and KS are phenotypically and genetically heterogeneous diseases in which the risk of transmission largely depends on the gene(s) responsible(s). Inheritance may be classically Mendelian yet more complex, oligogenic modes of transmission have also been described. The prevalence of oligogenicity has risen dramatically since the advent of massively parallel next-generation sequencing (NGS) in which tens, hundreds or thousands of genes are sequenced at the same time. NGS is medically and economically more efficient and more rapid than traditional Sanger sequencing, and is increasingly being used in medical practice. Thus it seems plausible that oligogenic forms of CHH/KS will be increasingly identified making genetic counseling even more complex. In this context, the main challenge will be to differentiate true oligogenism from situations when several rare variants that do not have a clear phenotypic effect are identified by chance. This review aims to summarize the genetics of CHH/KS and to discuss the challenges of oligogenic transmission but also its role in incomplete penetrance and variable expresivity in a perspective of genetic counseling.

Hypogonadotrophic hypogonadism, delayed puberty and risk for neurodevelopmental disorders

“…One hypothesis is that HH and delayed puberty may share some common aetiological factors with NDDs. Currently, more than 30 genes are implicated in the aetiology of HH and more genes are identified as the use of exome and genome sequencing is increasing . Mutations in some of these genes have also been described in ASD and other NDDs.…”

“…genes are implicated in the aetiology of HH and more genes are identified as the use of exome and genome sequencing is increasing. 1,5 Mutations in some of these genes have also been described in ASD and other NDDs. Case examples of these co-incidences include a stop gain in the ANOS1 gene (OMIM#300836) that was discovered in an individual diagnosed with ASD.…”

“…The disorder often co‐occurs with a range of other phenotypes, such as cleft lip/palate, hearing loss and skeletal anomalies. HH is considered a monogenic disorder; however, research shows that rarely there is a clear genotype‐phenotype correlation and complete penetrance among the mutation carriers . Currently, there are more than 30 genes implicated in the development of HH, including the ANOS1 ‐gene (MIM: 308700) and genes involved in the fibroblast growth factor signalling pathways …”

“…HH is considered a monogenic disorder; however, research shows that rarely there is a clear genotype-phenotype correlation and complete penetrance among the mutation carriers. 5 Currently, there are more than 30 genes implicated in the development of HH, including the ANOS1-gene (MIM: 308700) and genes involved in the fibroblast growth factor signalling pathways. 1 Neurodevelopmental disorders (NDDs) are a heterogeneous group of disabling childhood-onset behavioural conditions with an estimated prevalence of 10%.…”

Whole Exome Sequencing Revealed a Novel Nonsense Variant in the <b><i>GNRHR</i></b> Gene<b><i></i></b> Causing Normosmic Hypogonadotropic Hypogonadism in a Pakistani Family

“…have been related to CHH, and the number of disease-causing genes is increasing progressively with the usage of high-throughput sequencing techniques, which are outstanding approaches to evaluate massive genomic regions simultaneously in a short span of time [7]. Both monogenic and digenic/oligogenic mutations have been identified in CHH patients [8, 9]. Variations in the phenotypes have been reported even with the same mutation in the same kindred, which suggests that unknown genetic, epigenetic, and/or environmental factors may also be involved in CHH [10-15].…”