scholarly journals SUN-089 Novel Genetic and Biochemical Findings of DLK1 Deficiency in Children with Central Precocious Puberty - a Collaborative Brazilian-Spanish Study

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Luciana Ribeiro Montenegro ◽  
José Labarta ◽  
Maiara Piovesan ◽  
Ana Pinheiro Machado Canton ◽  
Raquel Corripio Collado ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Side Effects ◽  
Precocious Puberty ◽  
De Novo ◽  
Central Precocious Puberty ◽  
De Novo Mutation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Lhrh Analogues ◽  
Cranial Mri ◽  
Index Cases

Abstract Background: Delta-like 1 homolog (DLK1), also known as pre-adipocyte factor 1 (Pref-1), is part of the Notch signaling pathway that controls many developmental processes. Loss-of-function mutations of DLK1 have been identified in children with central precocious puberty (CPP), as well as in women who had precocious menarche (≤ 9 years) with an unfavorable metabolic profile. Objective: To investigate genetic and biochemical aspects of DLK1 in a cohort of children with CPP. Patients: A large cohort of Spanish children with idiopathic CPP (Spanish PUBERE Registry) was studied. Genomic DNA was obtained from 444 individuals, including 168 index cases with CPP and their close relatives. Automatic sequencing of the coding region (5 exons) of DLK1 was performed in all index cases. Serum DLK1 levels were measured by using a soluble DLK1 enzyme-linked immunosorbent assay (ELISA). Results: A rare allelic deletion (c.401_404 + 8del) of a splice site junction of DLK1 was identified in a girl with sporadic CPP. Pubertal signs appeared at 5.7 years of age with progressive puberty (basal LH: 1.7 mIU/mL, peak LH: 32.77 mIU/mL; basal FSH: 6.32 mIU/mL, peak FSH: 19.89 mIU/mL), BA/CA 1.7 years; normal cranial MRI). She received LHRH analogues (6.3 - 10.1 years of CA) with no side effects. At 14.9 years of age height and BMI are 152.9 cms and 18 kg/m2, respectively, presenting regular menses. Familial segregation analysis showed that the affected child was the only carrier of this deletion characterizing a de novo mutation (biological paternity and maternity were confirmed by microsatellite analysis). Serum DLK1 levels were undetectable (<0.4 ng/mL) in this girl, supporting that the deletion lead to complete lack of DLK1 production. Her father, mother and sister had normal serum DLK1 levels (ranged 6.36 ng/mL to 8.98 ng/mL). Two rare consecutive nucleotide changes in the promoter region of the DLK1 gene (c.-222 C>A and c.-223 G>A) were also identified in an adopted child with CPP. They are located in a transcription factor binding site for SP1 (a zinc finger transcription factor). Pubertal signs appeared at 6.7 years of age with progressive puberty (Basal LH: 0.5 mIU/mL, peak LH: 15.9 mIU/mL, basal FSH: 1.52 mIU/mL, peak FSH: 6.56 mIU/mL, BA/CA 1.4 years; normal cranial MRI). She is under therapy with LHRH analogues with no side effects. Conclusion: Novel DLK1 findings were identified in the Spanish cohort of children with CPP, reinforcing a significant role of this factor in human pubertal timing.

scholarly journals Idiopathic Central Precocious Puberty Associated with 11 MbDe NovoDistal Deletion of the Chromosome 9 Short Arm

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Mariangela Cisternino ◽  
Erika Della Mina ◽  
Laura Losa ◽  
Alexandra Madè ◽  
Giulia Rossetti ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
De Novo ◽  
Central Precocious Puberty ◽  
Chromosome 9 ◽  
Sexually Dimorphic ◽  
Idiopathic Central Precocious Puberty ◽  
Genome Wide ◽  
Causative Relationship ◽  
Sexually Dimorphic Expression ◽  
Dimorphic Expression

We report a girl with ade novodistal deletion of 9p affected by idiopathic central precocious puberty and intellectual disability. Genome-wide array-CGH revealed a terminal deletion of about 11 Mb, allowing to define her karyotype as 46; XX, del(9)(p23-pter). To our knowledge, this is the second reported case of precocious puberty associated with 9p distal deletion. A third case associates precocious puberty with a more proximal 9p deletion del(9)(p12p13,3). In our case, more than 40 genes were encompassed in the deleted region, among which, DMRT1 which is gonad-specific and has a sexually dimorphic expression pattern and ERMP1 which is required in rats for the organization of somatic cells and oocytes into discrete follicular structures. Although we cannot exclude that precocious puberty in our del(9p) patient is a coincidental finding, the report of the other two patients with 9p deletions and precocious puberty indeed suggests a causative relationship.

Insights from the genetic characterization of central precocious puberty associated with multiple anomalies

2020 ◽  
Author(s):  
Ana Pinheiro Machado Canton ◽  
Ana Cristina Victorino Krepischi ◽  
Luciana Ribeiro Montenegro ◽  
Silvia Costa ◽  
Carla Rosenberg ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Precocious Puberty ◽  
De Novo ◽  
Central Precocious Puberty ◽  
Genetic Defects ◽  
Chromosomal Microarray Analysis ◽  
National Council ◽  
Methylation Analysis ◽  
Candidate Regions ◽  
Selection Of

Abstract STUDY QUESTION Is there an (epi)genetic basis in patients with central precocious puberty (CPP) associated with multiple anomalies that unmasks underlying mechanisms or reveals novel genetic findings related to human pubertal control? SUMMARY ANSWER In a group of 36 patients with CPP associated with multiple phenotypes, pathogenic or likely pathogenic (epi)genetic defects were identified in 12 (33%) patients, providing insights into the genetics of human pubertal control. WHAT IS KNOWN ALREADY A few studies have described patients with CPP associated with multiple anomalies, but without making inferences on causalities of CPP. Genetic-molecular studies of syndromic cases may reveal disease genes or mechanisms, as the presentation of such patients likely indicates a genetic disorder. STUDY DESIGN, SIZE, DURATION This translational study was based on a genetic-molecular analysis, including genome-wide high throughput methodologies, for searching structural or sequence variants implicated in CPP and DNA methylation analysis of candidate regions. PARTICIPANTS/MATERIALS, SETTING, METHODS A cohort of 197 patients (188 girls) with CPP without structural brain lesions was submitted to a detailed clinical evaluation, allowing the selection of 36 unrelated patients (32 girls) with CPP associated with multiple anomalies. Pathogenic allelic variants of genes known to cause monogenic CPP (KISS1R, KISS1, MKRN3 and DLK1) had been excluded in the entire cohort (197 patients). All selected patients with CPP associated with multiple anomalies (n = 36) underwent methylation analysis of candidate regions and chromosomal microarray analysis. A subset (n = 9) underwent whole-exome sequencing, due to presenting familial CPP and/or severe congenital malformations and neurocognitive abnormalities. MAIN RESULTS AND THE ROLE OF CHANCE Among the 36 selected patients with CPP, the more prevalent associated anomalies were metabolic, growth and neurocognitive conditions. In 12 (33%) of them, rare genetic abnormalities were identified: six patients presented genetic defects in loci known to be involved with CPP (14q32.2 and 7q11.23), whereas the other six presented defects in candidate genes or regions. In detail, three patients presented hypomethylation of DLK1/MEG3:IG-DMR (14q32.2 disruption or Temple syndrome), resulting from epimutation (n = 1) or maternal uniparental disomy of chromosome 14 (n = 2). Seven patients presented pathogenic copy number variants: three with de novo 7q11.23 deletions (Williams–Beuren syndrome), three with inherited Xp22.33 deletions, and one with de novo 1p31.3 duplication. Exome sequencing revealed potential pathogenic variants in two patients: a sporadic female case with frameshift variants in TNRC6B and AREL1 and a familial male case with a missense substitution in UGT2B4 and a frameshift deletion in MKKS. LIMITATIONS, REASONS FOR CAUTION The selection of patients was based on a retrospective clinical characterization, lacking a longitudinal inclusion of consecutive patients. In addition, future studies are needed, showing the long-term (mainly reproductive) outcomes in the included patients, as most of them are not in adult life yet. WIDER IMPLICATIONS OF THE FINDINGS The results highlighted the relevance of an integrative clinical-genetic approach in the elucidation of mechanisms and factors involved in pubertal control. Chromosome 14q32.2 disruption indicated the loss of imprinting of DLK1 as a probable mechanism of CPP. Two other chromosomal regions (7q11.23 and Xp22.33) represented new candidate loci potentially involved in this disorder of pubertal timing. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grant number 2018/03198-0 (to A.P.M.C.) and grant number 2013/08028-1 (to A.C.V.K) from the São Paulo Research Foundation (FAPESP), and grant number 403525/2016-0 (to A.C.L.) and grant number 302849/2015-7 (to A.C.L.) and grant number 141625/2016-3 (to A.C.V.K) from the National Council for Scientific and Technological Development (CNPq). The authors have nothing to disclose. TRIAL REGISTRATION NUMBER N/A.

scholarly journals Yield of SCN5A sequencing in patients with related phenotypes studied in an inherited cardiovascular diseases unit

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
L Rodriguez Estevez ◽  
M Gallego Delgado ◽  
E Villacorta Arguelles ◽  
B Garcia Berrocal ◽  
V.E Vallejo Garcia ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Primary Prevention ◽  
Secondary Prevention ◽  
Atrial Flutter ◽  
Brugada Syndrome ◽  
De Novo ◽  
Conduction System ◽  
De Novo Mutation ◽  
Index Cases

Abstract   Mutations in SCN5A gene have been associated with different cardiac manifestations, so it is frequently tested in familial cardiovascular diseases. Our objective was to analyze the prevalence of pathogenic mutations (PM) in SCN5A in hereditary cardiovascular diseases and to describe the clinical characteristics of genetic carriers. SCN5A gene (NM_198056.2) was sequenced by NGS in panels of genes directed to each cardiac phenotype. We studied 219 index cases with theses phenotypes: 144 dilated/arrhythmogenic cardiomyopathy (DCM), 34 Brugada syndrome (BS), 19 idiopathic ventricular fibrillation (IVF), 10 long QT syndrome (LQTS), 9 sudden death with nondiagnostic necropsy and 3 advanced conduction system abnormalities. We identified 8 PM in 9 families, two of them have not been previously described: deletion of exons 1–16 of SCN5A and 15_27 in SCN10A and c.2665C>G. The prevalence of PM according to phenotypes was: 3 DCM (2%), 1 IVF (5%), 4 BS (12%) and 1 advanced conduction system abnormalities (33%). Additionally, we identified 4 variants of uncertain pathogenicity, two of them in the same patient with LQTS (compound heterozygosis). The index cases description is developed in Table 1. In our cohort the prevalence of PM in SCN5A is similar to those described in literature. The majority are associated with a combined phenotype (overlap syndrome of cardiac sodium channelopathy) which is characterized by supraventricular and ventricular arrhythmias and conduction system abnormalities, and some of them with DCM. Patients with BS had no additional manifestations, apart from ventricular arrhythmias in follow up. Table 1 Family number SCN5A Mutation Other mutations Sex/Age at diagnosis of index case (years) Phenotype of index case Devices (Age, years) Number of studied relatives (+ Genotype) Phenotypes in the family (Age, years) Family history 1 Deletion in exons 1_16 of SCN5A, y 15_27 of SCN10A SCN5A:c.3068G>T (VUS) Female/38 SCD due to nocturnal VF, Brugada syndrome Secondary prevention ICD (38) 2 (0) – SCD at paternal line 2 c.2254G>A LMNA:c.986G>A (VUS) Female/64 DCM Primary prevention ICD (69) 3 (1) Daughter PM (39) and atrial flutter SCD in first degree family members 3 c.2665C>G – Male/46 AF (27), AVB (36), VF (46) PM (36), secondary prevention ICD (46) 6 (3) Father PM (47) and atrial flutter Paternal grandfather SCD (53), cousin SCD (26) 4 c.2665C>G SCN5A:c.4057G>A (VUS) Male/ 64 DCM, VT, AF, atrial flutter (64) Secondary prevention (64), cardiac resynchronization therapy (68) 15 (7) Sister PM (26) None 5 c.3823G>A – Male/48 BS Primary prevention ICD (48) 0 (0) – SCD. Cousin with BS and ICD. Maternal grandmother with pacemaker. 6 c.4297G>T – Male/42 BS NO 4 (2) Sister Type 2 BS None 7 c.4783G>A – Male/14 Bifascicular heart block (right bundle branch block and left anterior division block), VT, atrial flutter. Primary prevention ICD (15) 3 (0) – None (de novo mutation) 8 c.4876C>T MYH7:c.4763G>A (VUS) Male/38 DCM, AVB, VF Secondary prevention ICD (38) 0 (0) – SCD in sibling (39 years) 9 c.4981G>A – Female/23 BS Primary prevention ICD (25), appropriate therapy in follow up 3 (0) – None (de novo mutation) AF: atrial fibrillation; AVB: atrioventricular block; BS: Brugada syndrome; DCM: dilated cardiomyopathy; ICD: implantable cardioverter defibrillator; PM: pacemaker; SCD: sudden cardiac death; VF: ventricular fibrillation; VT: ventricular tachycardia; VUS: Variant of uncertain significance. Funding Acknowledgement Type of funding source: None

Serum level of NPTX1 is independent of serum MKRN3 in central precocious puberty

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Hwal Rim Jeong ◽  
Jong Seo Yoon ◽  
Hye Jin Lee ◽  
Yeong Suk Shim ◽  
Min Jae Kang ◽  
...  
Keyword(s):  
Serum Level ◽  
Precocious Puberty ◽  
Standard Deviation Score ◽  
Ring Finger ◽  
Central Precocious Puberty ◽  
Serum Levels ◽  
Enzyme Linked Immunosorbent Assay ◽  
Loss Of Function ◽  
Early Puberty ◽  
Significant Difference

AbstractBackgroundMakorin ring finger protein 3 (MKRN3) is associated with the initiation of puberty, and loss of function mutation of MKRN3 is the most common genetic cause of central precocious puberty (CPP). A recent study reported that MKRN3 interacts with and suppresses neural pentraxin-1 precursor (NPTX1) activity via polyubiquitination during early puberty in the mouse hypothalamus.ObjectiveThis study investigated the correlation between serum NPTX1 and MKRN3 in CPP girls and predicted the potential role of NPTX1 in pubertal progression.MethodsIn this case–control study, we examined 34 girls diagnosed with CPP and 34 healthy prepubertal girls. Anthropometric and hormonal parameters were measured and serum levels of NPTX1 and MKRN3 were evaluated with commercial enzyme-linked immunosorbent assay kits.ResultsSerum MKRN3 level decreased significantly in CPP patients compared to controls (344.48 ± 333.77 and 1295.21 ± 780.80 pg/mL, respectively, p<0.001). Serum MKRN3 tended to decrease as Tanner breast stage increased. However, no significant difference was observed in serum NPTX1 levels between patients and controls (20.14 ± 31.75 ng/mL and 12.93 ± 8.28 ng/mL, respectively, p=0.248). The serum level of NPTX1 did not change significantly with the Tanner breast stage. Serum NPTX1 was correlated with the height standard deviation score (r=0.255; p<0.05), but was not correlated with serum MKRN3 level or the others. Conclusion: Although serum NPTX1 level was independent of serum MKRN3 level, the possibility they might be involved in the progression of puberty or CPP remains. Further research is needed to determine their role in the hypothalamus.

Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian–Spanish Study

2020 ◽  
Vol 105 (10) ◽  
pp. 3165-3172
Author(s):  
Luciana Montenegro ◽  
José I Labarta ◽  
Maira Piovesan ◽  
Ana P M Canton ◽  
Raquel Corripio ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
De Novo ◽  
Pubertal Timing ◽  
Central Precocious Puberty ◽  
Serum Levels ◽  
Metabolic Phenotype ◽  
Loss Of Function ◽  
Spanish Study ◽  
Allelic Deletion ◽  
Close Relatives

Abstract Background Central precocious puberty (CPP) has been associated with loss-of-function mutations in 2 paternally expressed genes (MKRN3 and DLK1). Rare defects in the DLk1 were also associated with poor metabolic phenotype at adulthood. Objective Our aim was to investigate genetic and biochemical aspects of DLK1 in a Spanish cohort of children with CPP without MKRN3 mutations. Patients A large cohort of children with idiopathic CPP (Spanish PUBERE Registry) was studied. Genomic deoxyribonucleic acid was obtained from 444 individuals (168 index cases) with CPP and their close relatives. Automatic sequencing of MKRN3 and DLK1 genes were performed. Results Five rare heterozygous mutations of MKRN3 were initially excluded in girls with familial CPP. A rare allelic deletion (c.401_404 + 8del) in the splice site junction of DLK1 was identified in a Spanish girl with sporadic CPP. Pubertal signs started at 5.7 years. Her metabolic profile was normal. Familial segregation analysis showed that the DLK1 deletion was de novo in the affected child. Serum DLK1 levels were undetectable (&lt;0.4 ng/mL), indicating that the deletion led to complete lack of DLK1 production. Three others rare allelic variants of DLK1 were also identified (p.Asn134=; g.-222 C&gt;A and g.-223 G&gt;A) in 2 girls with CPP. However, both had normal DLK1 serum levels. Conclusion Loss-of-function mutations of DLK1 represent a rare cause of CPP, reinforcing a significant role of this factor in human pubertal timing.

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