dc.description.abstract | The genetic control of puberty remains an important but mostly unanswered question. Late
pubertal timing affects over 2% of adolescents and is associated with adverse health
outcomes. Self-limited delayed puberty (DP) segregates in an autosomal dominant pattern
and is highly heritable; however, its neuroendocrine pathophysiology and genetic regulation
remain unclear.
The genetic control of puberty remains an important but mostly unanswered question. Late
pubertal timing affects over 2% of adolescents and is associated with adverse health
outcomes. Self-limited delayed puberty (DP) segregates in an autosomal dominant pattern
and is highly heritable; however, its neuroendocrine pathophysiology and genetic regulation
remain unclear.
Our large, accurately phenotyped cohort of patients with familial self-limited DP is a unique
resource with a relatively homogeneous genetic composition. I have utilised this cohort to
investigate the genetic variants segregating with the DP trait in these pedigrees. Whole
exome sequencing in eighteen probands and their relatives, and subsequent targeted
sequencing in an extended subgroup of the cohort, has revealed potential novel genetic
regulators of pubertal timing. In ten unrelated probands, I identified rare mutations in
IGSF10, a gene that is strongly expressed in the nasal mesenchyme during embryonic
migration of gonadotropin-releasing hormone (GnRH) neurons. IGSF10 knockdown both in
vitro and in a transgenic zebrafish model resulted in perturbed GnRH neuronal migration.
Loss-of-function mutations in IGSF10 were also identified in five patients with absent
puberty due to hypogonadotropic hypogonadism (HH). Additionally, I have identified and
investigated one rare, pathogenic mutation in HS6ST1 – a gene known to cause HH - in one
family with DP, and two rare variants in FTO – a gene implicated in the timing of menarche
in the general population - in 3 families. Further potentially pathogenic variants have
emerged from investigating candidate genes identified from microarray studies (LGR4,
SEMA6A and NEGR1) and from related clinical phenotypes (IGSF1).
Our large, accurately phenotyped cohort of patients with familial self-limited DP is a unique
resource with a relatively homogeneous genetic composition. I have utilised this cohort to
investigate the genetic variants segregating with the DP trait in these pedigrees. Whole
exome sequencing in eighteen probands and their relatives, and subsequent targeted
sequencing in an extended subgroup of the cohort, has revealed potential novel genetic
regulators of pubertal timing. In ten unrelated probands, I identified rare mutations in
IGSF10, a gene that is strongly expressed in the nasal mesenchyme during embryonic
migration of gonadotropin-releasing hormone (GnRH) neurons. IGSF10 knockdown both in
vitro and in a transgenic zebrafish model resulted in perturbed GnRH neuronal migration.
Loss-of-function mutations in IGSF10 were also identified in five patients with absent
puberty due to hypogonadotropic hypogonadism (HH). Additionally, I have identified and
investigated one rare, pathogenic mutation in HS6ST1 – a gene known to cause HH - in one
family with DP, and two rare variants in FTO – a gene implicated in the timing of menarche
in the general population - in 3 families. Further potentially pathogenic variants have
emerged from investigating candidate genes identified from microarray studies (LGR4,
SEMA6A and NEGR1) and from related clinical phenotypes (IGSF1). | en_US |