Context
Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP).
Objective
To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects.
Methods
Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group.
Results
Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ± 1.2 years in girls and 7.1 ± 1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ± 1.6 vs 1.6 ± 1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ± 1.8 vs 1.1 ± 1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization.
Conclusion
Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.
Background/Aims: Idiopathic central precocious puberty (ICPP) is the premature activation of the hypothalamic-pituitary-gonadal axis in the absence of organic disease. Up to now, just gain-of-function mutations of KISS1/KISS1R and loss-of-function mutations of the maternally imprinted gene MKRN3 are the known genetic causes of ICPP. Our intention is to evaluate variants present in genes related to the pubertal onset pathway that could act as disease-causing or predisposing variants. Methods: We studied the clinical exome of 20 patients diagnosed with ICPP using the Illumina platform. The bioinformatics analysis was performed using 2 different programs, and the variants were filtered according to a list of genes related to the gonadotropin-releasing hormone pathway. Results: In a “sporadic case,” we found a missense variant in MKRN3 NM_005664.3: c.203G>A, causing the protein change NP_005655.1:p.Arg68His, predicted as pathogenic by 2 informatics tools. The proband carrying this variant was diagnosed with ICPP at 7.75 years of age. We did not find any pathogenic variants in KISS1, KISS1R, LIN28, GNRH, GNRHR, TACR3, and TAC3. Conclusion:MKRN3 is the most frequent genetic cause of familial ICPP, so it is wise to screen for MKRN3 mutations in all patients with familial ICPP and in patients with an unclear paternal pubertal history.
<b><i>Background:</i></b> LZTR1 participates in RAS protein degradation, hence limiting the RAS/MAPK cascade. Pathogenic mutations in <i>LZTR1</i> (MIM:600574) have been described in a few patients with Noonan syndrome (NS). Three patients with <i>LZTR1</i> mutations of different genetic transmission and NS phenotype are herein characterized. <b><i>Clinical Cases:</i></b> Case 1 is a 5-year-old boy with NS phenotype. Sanger sequencing of <i>PTPN11</i> and <i>SOS1</i> identified no mutations. Whole exome sequencing (WES) detected a heterozygous missense mutation in <i>LZTR1</i>:c.742G>A (p.Gly248Arg) (exon 8, Kelch 4 functional domain). Bioinformatic algorithms predict a deleterious effect of this variant, previously described to cause NS. Case 2 is a 4-year-old boy with NS phenotype. Direct sequencing of 8 genes associated with NS identified no mutations. WES localized a homozygous missense mutation in <i>LZTR1</i>:c.2074T>C (p.Phe692Leu, exon 18). This mutation has not been reported before and is predicted to have a deleterious effect on the protein. Case 3 is an 8-year-old boy who shares NS phenotype with his mother. A multigene panel for RASopathies showed a heterozygous missense variant in <i>LZTR1</i>:c.730T>C (p.Ser244Pro) (exon 8; Kelch 4 functional domain) that was maternally inherited. This variant has not been previously described; however, in silico predictors classify it as deleterious. Familial segregation suggests its pathogenicity. <b><i>Conclusions:</i></b> The molecular approach for syndromic phenotypes associated with various genes should involve complete/updated panels or WES rather than gene-by-gene sequencing. RASopathy genetic panels should incorporate <i>LZTR1</i>. Patients with pathogenic mutations in <i>LZTR1</i> exhibit a characteristic NS gestalt but variable cardiac, height, and neurodevelopment expressions, with recessive inheritance possibly associating with a more severe phenotype.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.