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Lysozyme-derived (ALys) amyloidosis is a rare type of hereditary amyloidosis. Nine amyloidogenic variants and ∼30 affected families have been described worldwide. The most common manifestations are renal dysfunction, gastrointestinal tract symptoms, and sicca syndrome. We report on the clinical course of ten patients from six families representing one of the largest cohorts published so far. Seven patients carried the W64R variant showing the whole spectrum of ALys-associated symptoms. Two patients—a mother-son pair—carried a novel lysozyme variant, which was associated with nephropathy and peripheral polyneuropathy. In accordance with previous findings, the phenotype resembled within these families but did not correlate with the genotype. To gain insights into the effect of the variants at the molecular level, we analysed the structure of lysozyme and performed comparative computational predictions on aggregation propensity and conformational stability. Our study supports that decreased conformational stability is a key factor for lysozyme variants to be prone to aggregation. In summary, ALys amyloidosis is a very rare, but still heterogeneous disease that can manifest at an early age. Our newly identified lysozyme variant is associated with nephropathy and peripheral polyneuropathy. Further research is needed to understand its pathogenesis and to enable the development of new treatments. [ABSTRACT FROM AUTHOR]

The plasma protein transthyretin (TTR) can aggregate into insoluble amyloid fibrils causing systemic amyloidosis (ATTR amyloidosis) in patients carrying a variant TTR protein. If new variants arise, it is crucial to clarify whether they are disease-associated or benign. In this study, we further functionally characterize three new and unclassified TTR variants (Thr40Asn, Phe64Val and the described but not functionally assessed variant Leu12Val), using a simplified, fast isoelectric focusing (IEF) approach. After validating the system with known TTR variants, we assessed the sera of five patients carrying these new TTR variants in a heterozygous state. All three variants showed aberrant banding patterns that were similar to those of other well-characterized TTR variants, including the common Val30Met variant that causes ATTR amyloidosis. In addition to a clear band corresponding to monomeric wild-type TTR, we observed an additional variant band at the cathodal side of the IEF gel. These results indicate conformational instability of the new Thr40Asn, Phe64Val and Leu12Val variants. Together with the clinical and immunohistological data of these patients and affected family members, as well as the absence of these variants in human genetic mutation databases, our results strongly hint that these variants are amyloidogenic and therefore probably disease-associated. These findings have implications for patient therapy and for genetic counselling of family members. [ABSTRACT FROM AUTHOR]

Background: Mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene can lead to hereditary pulmonary arterial hypertension (HPAH) and are detected in more than 80% of cases with familial aggregation of the disease. Factors determining disease penetrance are largely unknown. Methods: A mean clinical follow-up of 12 years was accomplished in 46 family members including echocardiography, stress-Dopplerechocardiography and genetic analysis of TGF-β pathway genes. Right heart catheterization and RNA-analysis was performed in members with pathological findings. Results: Manifest HPAH was diagnosed in 8 members, 4 were already deceased, two died during the follow-up, two are still alive. Normal pulmonary artery systolic pressure at rest but hypertensive response to exercise has been identified in 19 family members. Analysis of BMPR2 transcripts revealed aberrant splicing due to an insertion of an intronic Alu element adjacent to exon 6. All HPAH patients and 12 further asymptomatic family members carried this insertion. During follow-up two family members carrying hypertensive response and the Alu insertion developed manifest HPAH. Conclusion: This is the first report of an intronic BMPR2 mutation due to an Alu element insertion causing HPAH in a large family which has been confirmed on RNA-level. Only those members that carried both hypertensive response and the mutation developed manifest HPAH during follow-up. Our findings highlight the importance of including further methods such as RNA analysis into the molecular genetic diagnostic of PAH patients. They suggest that at least in some families hypertensive response may be an additional risk factor for disease manifestation and penetrance. [ABSTRACT FROM AUTHOR]

Pathogenic variants have been identified in 85% of heritable pulmonary arterial hypertension (PAH) patients. These variants were mainly located in the bone morphogenetic protein receptor 2 (BMPR2) gene. However, the penetrance of BMPR2 variants was reduced leading to a disease manifestation in only 30% of carriers. In these PAH patients, further modifiers such as additional pathogenic BMPR2 promoter variants could contribute to disease manifestation. Therefore, the aim of this study was to identify BMPR2 promoter variants in PAH patients and to analyze their transcriptional effect on gene expression and disease manifestation. BMPR2 promoter variants were identified in PAH patients and cloned into plasmids. These were transfected into human pulmonary artery smooth muscle cells to determine their respective transcriptional activity. Nine different BMPR2 promoter variants were identified in seven PAH families and three idiopathic PAH patients. Seven of the variants (c.-575A>T, c.-586dupT, c.-910C>T, c.-930_-928dupGGC, c.-933_-928dupGGCGGC, c.-930_-928delGGC and c.-1141C>T) led to a significantly decreased transcriptional activity. This study identified novel BMPR2 promoter variants which may affect BMPR2 gene expression in PAH patients. They could contribute to disease manifestations at least in some families. Further studies are needed to investigate the frequency of BMPR2 promoter variants and their impact on penetrance and disease manifestation. [ABSTRACT FROM AUTHOR]

Fragile X mental retardation protein (FMRP) is a translational repressor encoded by FMR1. It targets bone morphogenetic protein receptor type II (BMPR2), which regulates granulosa cell (GC) function and follicle development. However, whether this interaction affects folliculogenesis remains unclear. Therefore, this study investigated the potential effect of FMRP-BMPR2 dysregulation in ovarian reserves and infertility. COV434 cells and patient-derived GCs were used to evaluate FMRP and BMPR2 expression. Similarly, FMR1, BMPR2, LIMK1, and SMAD expression were evaluated in GCs with normal (NOR) and poor (POR) ovarian responses. FMRP and BMPR2 were expressed in both cell types. They were co-localized to the nuclear membrane of COV434 cells and cytoplasm of primary GCs. FMR1 silencing increased the mRNA and protein levels of BMPR2. However, the mRNA levels of FMR1 and BMPR2 were significantly lower in the POR group. FMR1 and BMPR2 levels were strongly positively correlated in the NOR group but weakly correlated in the POR group. Additionally, SMAD9 expression was significantly reduced in the POR group. This study highlights the crucial role of FMR1/FMRP in the regulation of BMPR2 expression and its impact on ovarian function. These findings indicate that the disruption of FMRP-BMPR2 interactions may cause poor ovarian responses and infertility. [ABSTRACT FROM AUTHOR]

Glutaric aciduria type 1 (GA-1) is a rare but treatable autosomal-recessive neurometabolic disorder of lysin metabolism caused by biallelic pathogenic variants in glutaryl-CoA dehydrogenase gene (GCDH) that lead to deficiency of GCDH protein. Without treatment, this enzyme defect causes a neurological phenotype characterized by movement disorder and cognitive impairment. Based on a comprehensive literature search, we established a large dataset of GCDH variants using the Leiden Open Variation Database (LOVD) to summarize the known genotypes and the clinical and biochemical phenotypes associated with GA-1. With these data, we developed a GCDH-specific variation classification framework based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. We used this framework to reclassify published variants and to describe their geographic distribution, both of which have practical implications for the molecular genetic diagnosis of GA-1. The freely available GCDH-specific LOVD dataset provides a basis for diagnostic laboratories and researchers to further optimize their knowledge and molecular diagnosis of this rare disease. [ABSTRACT FROM AUTHOR]

Iron deficiency is common in idiopathic and heritable pulmonary arterial hypertension patients (I/HPAH). A previous report suggested a dysregulation of the iron hormone hepcidin, which is controlled by BMP/SMAD signaling involving the bone morphogenetic protein receptor 2 (BMPR‐II). Pathogenic variants in the BMPR2 gene are the most common cause of HPAH. Their effect on patients' hepcidin levels has not been investigated. The aim of this study was to assess whether iron metabolism and regulation of the iron regulatory hormone hepcidin was disturbed in I/HPAH patients with and without a pathogenic variant in the gene BMPR2 compared to healthy controls. In this explorative, cross‐sectional study hepcidin serum levels were quantified by enzyme‐linked immunosorbent assay. We measured iron status, inflammatory parameters and hepcidin modifying proteins such as IL6, erythropoietin, and BMP2, BMP6 in addition to BMPR‐II protein and mRNA levels. Clinical routine parameters were correlated with hepcidin levels. In total 109 I/HPAH patients and controls, separated into three groups, 23 BMPR2 variant‐carriers, 56 BMPR2 noncarriers and 30 healthy controls were enrolled. Of these, 84% had iron deficiency requiring iron supplementation. Hepcidin levels were not different between groups and corresponded to the degree of iron deficiency. The levels of IL6, erythropoietin, BMP2, or BMP6 showed no correlation with hepcidin expression. Hence, iron homeostasis and hepcidin regulation was largely independent from these parameters. I/HPAH patients had a physiologically normal iron regulation and no false elevation of hepcidin levels. Iron deficiency was prevalent albeit independent of pathogenic variants in the BMPR2 gene. [ABSTRACT FROM AUTHOR]

Congenital cataract (CC) is one of the most important causes for blindness or visual impairment in infancy. A substantial proportion of isolated CCs has monogenic causes. The disease is genetically heterogeneous, and all Mendelian modes of inheritance have been reported. We mapped a locus for isolated CC on 19p13.1-q13.2 in a distantly consanguineous German family with two sisters affected by dense white cataracts. Whole-exome sequencing identified a homozygous nonsense variant c.4489C>T (p.(R1497*)) in SIPA1L3 (signal-induced proliferation-associated 1 like 3) in both affected children. SIPA1L3 encodes a GTPase-activating protein (GAP), which interacts with small GTPases of the Rap family via its Rap-GAP-domain. The suggested role of Rap GTPases in cell growth, differentiation and organization of the cytoskeleton in the human lens, and lens-enriched expression of the murine ortholog gene Sipa1l3 in embryonic mice indicates that this gene is crucial for early lens development. Our results provide evidence that sequence variants in human SIPA1L3 cause autosomal recessive isolated CC and give new insight into the molecular pathogenesis underlying human cataracts. [ABSTRACT FROM AUTHOR]

Background: The protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates early follicular activation and follicular pool maintenance in female germline cells. Fragile X mental retardation 1 (FMR1) regulates folliculogenesis and it is variably expressed in patients with Premature Ovary Insufficiency. FMR1 expression is supposed to be linked to AKT/mTOR signaling in an ovarian response dependent manner as demonstrated in recent invitro and invivo studies in the female germline invitro and invivo. Methods: We evaluated changes in the expression of AKT/mTOR signaling pathway genes by real time PCR in the peripheral blood of 74 patients with Premature Ovarian Insufficiency and 56 fertile controls and correlated their expression with FMR1 expression. Results: Expression of the genes AKT1, TSC2, mTOR, and S6K was significantly more abundant in patients with POI than in the controls. For AKT1, TSC2 and mTOR, gene expression was not affected by FMR1-CGG repeat number in the 5´-untranslated region. FMR1 and S6K expression levels, however, were significantly upregulated in patients with POI and an FMR1 premutation. Independent of a premutation, expression of mTOR, S6K, and TSC2 was significantly correlated with that of FMR1 in all patients. Furthermore, when grouped according to ovarian reserve, this effect remained significant only for mTOR and S6K, with higher significance note in patients with Premature Ovarian Insufficiency than in the controls. Conclusions: In Premature ovarian insufficiency patients, activation of AKT/mTOR signaling pathway is remarkable and putatively pathognomonic. Additionally, it seems to be triggered by an FMR1/mTOR/S6K linkage mechanism, most relevant in premutation carriers. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) can be caused by pathogenic variants in the gene bone morphogenetic protein receptor 2 (BMPR2). While BMPR2 protein expression levels are known to be reduced in the lung tissue of heritable PAH (HPAH) patients, a systematic study evaluating expression in more easily accessible blood samples and its clinical relevance is lacking. Thus, we analyzed the BMPR2 mRNA expression in idiopathic/HPAH patients and healthy controls in blood by quantitative polymerase chain reaction and protein expression by enzyme-linked immunosorbent assay. Clinical parameters included right heart catherization, echocardiography, six-minute walking test and laboratory tests. BMPR2 variant-carriers (n = 23) showed significantly lower BMPR2 mRNA expression in comparison to non-carriers (n = 56) and healthy controls (n = 30; p < 0.0001). No difference in BMPR2 protein expression was detected. Lower BMPR2 mRNA expression correlated significantly with greater systolic pulmonary artery pressure and pulmonary vascular resistance. Higher BMPR2 mRNA expression correlated with greater glomerular filtration rate, cardiac index and six-minute walking distance. We demonstrated the feasibility to assess BMPR2 expression in blood and, for the first time, that BMPR2 mRNA expression levels are significantly reduced in variant carriers and correlated with clinical parameters. Further studies may evaluate the usefulness of BMPR2 mRNA expression in blood as a new marker for disease severity. [ABSTRACT FROM AUTHOR]

Background: The protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates early follicular activation and follicular pool maintenance in female germline cells. Fragile X mental retardation 1 (FMR1) regulates folliculogenesis and it is variably expressed in patients with Premature Ovary Insufficiency. FMR1 expression is supposed to be linked to AKT/mTOR signaling in an ovarian response dependent manner as demonstrated in recent invitro and invivo studies in the female germline invitro and invivo. Methods: We evaluated changes in the expression of AKT/mTOR signaling pathway genes by real time PCR in the peripheral blood of 74 patients with Premature Ovarian Insufficiency and 56 fertile controls and correlated their expression with FMR1 expression. Results: Expression of the genes AKT1, TSC2, mTOR, and S6K was significantly more abundant in patients with POI than in the controls. For AKT1, TSC2 and mTOR, gene expression was not affected by FMR1-CGG repeat number in the 5´-untranslated region. FMR1 and S6K expression levels, however, were significantly upregulated in patients with POI and an FMR1 premutation. Independent of a premutation, expression of mTOR, S6K, and TSC2 was significantly correlated with that of FMR1 in all patients. Furthermore, when grouped according to ovarian reserve, this effect remained significant only for mTOR and S6K, with higher significance note in patients with Premature Ovarian Insufficiency than in the controls. Conclusions: In Premature ovarian insufficiency patients, activation of AKT/mTOR signaling pathway is remarkable and putatively pathognomonic. Additionally, it seems to be triggered by an FMR1/mTOR/S6K linkage mechanism, most relevant in premutation carriers. [ABSTRACT FROM AUTHOR]

Fragile X-associated primary ovarian insufficiency (FXPOI) is characterized by oligo/amenorrhea and hypergonadotropic hypogonadism and is caused by the expansion of the CGG repeat in the 5′UTR of Fragile X Mental Retardation 1 (FMR1). Approximately 20% of women carrying an FMR1 premutation (PM) allele (55–200 CGG repeat) develop FXPOI. Repeat Associated Non-AUG (RAN)-translation dependent on the variable CGG-repeat length is thought to cause FXPOI, due to the production of a polyglycine-containing FMR1 protein, FMRpolyG. Peripheral blood monocyte cells (PBMCs) and granulosa cells (GCs) were collected to detect FMRpolyG and its cell type-specific expression in FMR1 PM carriers by immunofluorescence staining (IF), Western blotting (WB), and flow cytometric analysis (FACS). For the first time, FMRpolyG aggregates were detected as ubiquitin-positive inclusions in PBMCs from PM carriers, whereas only a weak signal without inclusions was detected in the controls. The expression pattern of FMRpolyG in GCs was comparable to that in the lymphocytes. We detected FMRpolyG as a 15- to 25-kDa protein in the PBMCs from two FMR1 PM carriers, with 124 and 81 CGG repeats. Flow cytometric analysis revealed that FMRpolyG was significantly higher in the T cells from PM carriers than in those from non-PM carriers. The detection of FMRpolyG aggregates in the peripheral blood and granulosa cells of PM carriers suggests that it may have a toxic potential and an immunological role in ovarian damage in the development of FXPOI. [ABSTRACT FROM AUTHOR]

Hereditary transthyretin amyloidosis is caused by pathogenic variants in the TTR gene and typically manifests, alongside cardiac and other organ dysfunctions, with a rapidly progressive sensorimotor and autonomic polyneuropathy (ATTRv-PN) leading to severe disability. While most prospective studies have focussed on endemic ATTRv-PN, real-world data on non-endemic, mostly late-onset ATTRv-PN are limited. This retrospective study investigated ATTRv-PN patients treated at the Amyloidosis Centre of Heidelberg University Hospital between November 1999 and July 2020. Clinical symptoms, survival, prognostic factors and efficacy of treatment with tafamidis were analysed. Neurologic outcome was assessed using the Coutinho ATTRv-PN stages, and the Peripheral Neuropathy Disability (PND) score. Of 346 subjects with genetic TTR variants, 168 patients had symptomatic ATTRv-PN with 32 different TTR variants identified. Of these, 81.6% had the late-onset type of ATTRv-PN. Within a mean follow-up period of 4.1 ± 2.8 years, 40.5% of patients died. Baseline plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) ≥900 ng/l (HR 3.259 [1.421–7.476]; p =.005) was the main predictor of mortality in multivariable analysis. 64 patients were treated with tafamidis and presented for regular follow-up examinations. The therapeutic benefit of tafamidis was more pronounced when treatment was started early in ATTRv-PN stage 1 (PND scores II vs. I; HR 2.718 [1.258–5.873]; p =.011). In non-endemic, mostly late-onset ATTRv-PN, cardiac involvement assessed by NT-proBNP is a strong prognosticator for overall survival. Long-term treatment with tafamidis is safe and efficacious. Neurologic disease severity at the start of treatment is the main predictor for ATTRv-PN progression on tafamidis. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented discussing the case study of a Hodgkin's lymphoma patient who suffered from ornithine transcarbamylase (OTC) deficiency based on a hemizygous p.R277W mutation causing hyperammonemic crisis during his treatment for Hodgkin's lymphoma.

Background: Exaggerated pulmonary arterial hypertension (PAH) is a hallmark of high-altitude pulmonary edema (HAPE). The objective of this study was therefore to investigate genetic predisposition to HAPE by analyzing PAH candidate genes in a HAPE-susceptible (HAPE-S) family and in unrelated HAPE-S mountaineers. Materials and Methods: Eight family members and 64 mountaineers were clinically and genetically assessed using a PAH-specific gene panel for 42 genes by next-generation sequencing. Results: Two otherwise healthy family members, who developed re-entry HAPE at 3640 m during childhood, carried a likely pathogenic missense mutation (c.1198T>G p.Cys400Gly) in the Janus Kinase 2 (JAK2) gene. One of them progressed to a mild form of PAH at the age of 23 years. In two of the 64 HAPE-S mountaineers likely pathogenic variants have been detected, one missense mutation in the Cytochrome P1B1 gene, and a deletion in the Histidine-Rich Glycoprotein (HRG) gene. Conclusions: This is the first study identifying an inherited missense mutation of a gene related to PAH in a family with re-entry HAPE showing a progression to borderline PAH in the index patient. Likely pathogenic variants in 3.1% of HAPE-S mountaineers suggest a genetic predisposition in some individuals that might be linked to PAH signaling pathways. [ABSTRACT FROM AUTHOR]

Granulosa cells (GCs) play a major role in folliculogenesis and are crucial for oocyte maturation and growth. In these cells, the mTOR/AKT signalling pathway regulates early folliculogenesis by maintaining the dormancy of primordial follicles, while FSH induces their further differentiation and maturation. Because changes in number of CGG triplets in FMR1 exon 1 (below or beyond normal values of 26–34 triplets) affect ovarian reserve and pre-mutations containing >54 CGG triplets represent a known risk factor for premature ovarian insufficiency/failure, we investigated in the human GC model (COV434) how FMR1 /FMRP and mTOR/AKT are expressed and potentially interact during GC proliferation. As FMR protein (FMRP) is expressed mainly in human ovarian GCs, we used these after inducing their proliferation using recombinant FSH (rFSH) and the repression of the mTOR/AKT signalling pathway. We showed that AKT and mTOR expression levels significantly increase after stimulation with rFSH, while S6K and FMR1 expression decrease. After inhibiting mTOR and AKT, FMR1 and S6K expression significantly increased. Only AKT inhibition led to decreased FMRP levels, as expected due to the known FMR1 /FMRP negative feedback loop. But rFSH and the mTOR inhibition increased them, indicating a decoupling of this FMR1/ FMRP negative feedback loop in our model system. [ABSTRACT FROM AUTHOR]

Mutations in GNAO1 (guanine nucleotide-binding protein, alpha-activating activity polypeptide O) were recently identified as being causative for early epileptic encephalopathy. Since then approximately 27 patients with severe developmental delay and different neurological phenotypes for epilepsy and involuntary movement disorder have been reported. We report four additional patients with mutations in GNAO1 including a report of siblings of different sex harboring the same de novo mutation (c.736G > A, p.Glu246Lys) but showing differences in phenotype with pronounced dystonia in the boy and epilepsy in his sister. Another de novo mutation in GNAO1 (c.607G > A, p.Gly203Arg) was identified in two unrelated girls with severe epilepsy. Both girls later also developed severe dystonia with severe nonepileptic spasms. An extensive review of published cases revealed that epilepsy was reported in only one male patient so far. Thus it appears possible that epilepsy is a sex-dependent phenotypic feature of GNAO1-related diseases. [ABSTRACT FROM AUTHOR]

Whole exome sequencing (WES) is well established in research and is now being introduced into clinically indicated diagnostics (so-called clinical exomes). We evaluated the diagnostic yield and clinical implications of WES in 72 patients from 60 families with undiagnosed neurodevelopmental disorders (NDD), neurometabolic disorders, and dystonias. Pathogenic or likely pathogenic variants leading to a molecular diagnosis could be identified in 21 of the 60 families (overall 35%, in 36% of patients with NDD, in 43% of patients with neurometabolic disorders, in 25% of patients with dystonias). In one family two coexisting autosomal recessive diseases caused by homozygous pathogenic variants in two different genes were diagnosed. In another family, a homozygous frameshift variant in STRADA was found to cause a severe NDD with early onset epilepsy, brain anomalies, hypotonia, heart defect, nephrocalcinosis, macrocephaly and distinctive facies so far designated as PMSE (polyhydramnios, megalencephaly, symptomatic epilepsy) syndrome. In 7 of the 21 families with a molecular diagnosis the pathogenic variants were only identified by clinical follow-up, manual reevaluation of the literature, a change of filter setting, and/or reconsideration of inheritance pattern. Most importantly, clinical implications included management changes in 8 cases and impact on family planning in 20 families with a molecular diagnosis. This study shows that reevaluation and follow-up can improve the diagnostic rate and that WES results have important implications on medical management and family planning. Furthermore, we could confirm STRADA as a gene associated with syndromic ID but find it questionable if the current designation as PMSE depicts the most important clinical features. [ABSTRACT FROM AUTHOR]

Heritable pulmonary arterial hypertension (HPAH) is an autosomal dominantly inherited disease caused by mutations in the bone morphogenic protein receptor 2 (BMPR2) gene and/or genes of its signalling pathway in approximately 85% of patients. We clinically and genetically analysed an HPAH family without mutations in previously described pulmonary arterial hypertension (PAH) genes. Clinical assessment included electrocardiogram, lung function, blood gas analysis, chest X-ray, laboratory testing, echocardiography and right heart catheterization in case of suspected disease. Genetic diagnostics were performed using a PAH-specific gene panel including all known 12 PAH genes and 20 further candidate genes by next-generation sequencing (NGS). HPAH was invasively confirmed in two sisters and their father who died aged 32 years. No signs of HPAH were detected in five first-degree family members. Both sisters were lung transplanted and remained stable during a follow-up of >20 years. We detected a novel missense mutation in the Krüppel-like factor 2 (KLF2) likely leading to a disruption of gene function. The same KLF2 mutation has been described as a recurrent somatic mutation in B-cell lymphoma. Neither the healthy family members carried the mutation nor >120000 controls. These findings point to KLF2 as a new PAH gene. Further studies are needed to assess frequency and implication of KLF2 mutations in PAH patients. [ABSTRACT FROM AUTHOR]

Metaphase karyotyping is an established diagnostic standard in acute myeloid leukemia (AML) for risk stratification. One of the cytogenetic findings in AML is structurally highly abnormal marker chromosomes. In this study, we have assessed frequency, cytogenetic characteristics, prognostic impact, and underlying biological origin of marker chromosomes. Given their inherent gross structural chromosomal damage, we speculated that they may arise from chromothripsis, a recently described phenomenon of chromosome fragmentation in a single catastrophic event. In 2 large consecutive prospective, randomized, multicenter, intensive chemotherapy trials (AML96, AML2003) from the Study Alliance Leukemia, marker chromosomes were detectable in 165/1026 (16.1%) of aberrant non-core-binding-factor (CBF) karyotype patients. Adverse-risk karyotypes displayed a higher frequency of marker chromosomes (26.5% in adverse-risk, 40.3% in complex aberrant, and 41.2% in abnormality(17p) karyotypes, P < .0001 each). Marker chromosomes were associated with a poorer prognosis compared with other non-CBF aberrant karyotypes and led to lower remission rates (complete remission 1 complete remission with incomplete recovery), inferior event-free survival as well as overall survival in both trials. In multivariate analysis, marker chromosomes independently predicted poor prognosis in the AML96 trial ≤60 years. As detected by array comparative genomic hybridization, about one-third of marker chromosomes (18/49) had arisen from chromothripsis, whereas this phenomenon was virtually undetectable in a control group of marker chromosome-negative complex aberrant karyotypes (1/34). The chromothripsis-positive cases were characterized by a particularly high degree of karyotype complexity, TP53 mutations, and dismal prognosis. In conclusion, marker chromosomes are indicative of chromothripsis and associated with poor prognosis per se and not merely by association with other adverse cytogenetic features. [ABSTRACT FROM AUTHOR]

Metaphase karyotyping is an established diagnostic standard in acute myeloid leukemia (AML) for risk stratification. One of the cytogenetic findings in AML is structurally highly abnormal marker chromosomes. In this study, we have assessed frequency, cytogenetic characteristics, prognostic impact, and underlying biological origin of marker chromosomes. Given their inherent gross structural chromosomal damage, we speculated that they may arise from chromothripsis, a recently described phenomenon of chromosome fragmentation in a single catastrophic event. In 2 large consecutive prospective, randomized, multicenter, intensive chemotherapy trials (AML96, AML2003) from the Study Alliance Leukemia, marker chromosomes were detectable in 165/1026 (16.1%) of aberrant non-core-binding-factor (CBF) karyotype patients. Adverse-risk karyotypes displayed a higher frequency of marker chromosomes (26.5% in adverse-risk, 40.3% in complex aberrant, and 41.2% in abnormality(17p) karyotypes, P < .0001 each). Marker chromosomes were associated with a poorer prognosis compared with other non-CBF aberrant karyotypes and led to lower remission rates (complete remission + complete remission with incomplete recovery), inferior event-free survival as well as overall survival in both trials. In multivariate analysis, marker chromosomes independently predicted poor prognosis in the AML96 trial S60 years. As detected by array comparative genomic hybridization, about one-third of marker chromosomes (18/49) had arisen from chromothripsis, whereas this phenomenon was virtually undetectable in a control group of marker chromosome-negative complex aberrant karyotypes (1/34). The chromothripsis-positive cases were characterized by a particularly high degree of karyotype complexity, TP53 mutations, and dismal prognosis. In conclusion, marker chromosomes are indicative of chromothripsis and associated with poor prognosis per se and not merely by association with other adverse cytogenetic features. [ABSTRACT FROM AUTHOR]

The article discusses research on the effectiveness of doxycycline in treating a 42-year-old male patient with ATTR amyloidosis, which was caused by ATTRY69H mutation in exon of the transthyretin (TTR) gene, with predominant leptomeningeal manifestation. The details of the medical condition of the patient are presented. The researchers noted the improvement in the patient's cognitive function and walking with doxycycline treatment.

In the present study we developed a new specific gene panel for pulmonary arterial hypertension (PAH) including major disease genes and further candidates. We assessed 37 patients with invasively confirmed PAH and five relatives of affected patients for genetic testing. A new PAH-specific gene panel was designed using next generation sequencing (NGS) including 12 known disease genes and 17 further candidates. Any potential pathogenic variants were reassessed by Sanger sequencing. Twenty-two of the 37 patients (59%) had a mutation in BMPR2, ALK1, ENG or EIF2AK4 genes identified by panel and Sanger sequencing. In addition, 12 unclassified variants were identified in seven genes (known and candidate genes). A sensitivity of 100% was met after quality parameters were adjusted. Specificity increased to 100% when Sanger technique was added as a routine validation. The new PAH-specific gene panel developed in the present study allowed for the first time the assessment of all known PAH genes and further candidates at once and markedly reduced overall sequencing time and costs. Sensitivity and specificity reached 100% when Sanger sequencing was additionally applied. Thus, this technique will potentially change the routine diagnostic genetic testing in PAH patients. [ABSTRACT FROM AUTHOR]

Background: Mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene have recently been identified in recessively inherited veno-occlusive disease. In this study we assessed if EIF2AK4 mutations occur also in a family with autosomal dominantly inherited pulmonary arterial hypertension (HPAH) and incomplete penetrance of bone morphogenic protein receptor 2 (BMPR2) mutations. Methods: Clinical examinations in a family with 10 members included physical examination, electrocardiogram, (stress)-echocardiography and lung function. Manifest PAH was confirmed by right heart catheterisation in three affected subjects. Genetic analysis was performed using a new PAH-specific gene panel analysis with next generation sequencing of all known PAH and further candidate genes. Identified variants were confirmed by Sanger sequencing. Results: All living family members with manifest HPAH carried two pathogenic heterozygous mutations: a frame shift mutation in the BMPR2 gene and a novel splice site mutation in the EIF2AK4 gene. Two family members who carried the BMPR2 mutation only did not develop manifest HPAH. Conclusions: This is the first study suggesting that EIF2AK4 can also contribute to autosomal dominantly inherited HPAH. Up to now it has only been identified in a recessive form of HPAH. Only those family members with a co-occurrence of two mutations developed manifest HPAH. Thus, the EIF2AK4 and BMRPR2 mutations support the "second hit" hypothesis explaining the variable penetrance of HPAH in this family. Hence, the assessment of all known PAH genes in families with a known mutation might assist in predictions about the clinical manifestation in so far non-affected mutation carriers. [ABSTRACT FROM AUTHOR]

Background: Children and patients with cognitive deficits may find it difficult to understand the implication of research. In the European Union (EU), clinical studies outside the EU directives concerning medicinal products or medical devices, i.e., “miscellaneous clinical studies”, have no legally mandated timelines for institutional review boards’ (IRB) decisions. Goal: To evaluate the review process of IRBs for two different “miscellaneous” multicenter clinical research protocols involving vulnerable subjects (children and adult stroke patients). Methods: Descriptive and comparative statistics. Protocol 1 is a prospective, multicenter, cross-sectional screening study of a symptomatic pediatric population at risk for Fabry disease involving genetic testing (NCT02152189). Protocol 2 is a prospective, multicenter, randomized, controlled, open-label, blinded endpoint post-market study to evaluate the effectiveness of stent retrievers (NCT02135926). After having obtained positive initial IRB votes at the main study site, both protocols were subsequently submitted to the remaining IRBs. Results: Protocol 1 was submitted to 19 IRBs. No IRB objected to the study. Median time-to-final vote was 34 (IQR 10–65; range 0 to 130) days. Two IRBs accepted the coordinating center’s IRB votes without re-evaluation. Changes to the informed consent documents were asked by 7/19 IRBs, amendments to the protocol by 2. Protocol 2 was submitted to 16 IRBs. Fifteen decisions were made. No IRB objected to the study. Median time-to final vote was 59 (IQR 10 to 65; range 0 to 128) days, which was not statistically significantly different compared with protocol 1 (Wilcoxon test). Two IRBs accepted a previous IRB decision and did not conduct an independent review. Eight/16 IRBs required changes to the informed consent documents; two IRBs recommended an amendment of the protocol. Conclusion: Both clinical research protocols involving vulnerable populations were well accepted. IRB workflows and decision times varied substantially. Some IRBs accepted a previous IRB decision without the necessity of another reevaluation process. Requested changes were focused on the informed consent documents. A more standardized approach across jurisdictions is desirable. [ABSTRACT FROM AUTHOR]

Background: Hereditary pulmonary arterial hypertension (HPAH) can be caused by autosomal dominant inherited mutations of TGF-β genes, such as the bone morphogenetic protein receptor 2 (BMPR2) and Endoglin (ENG) gene. Additional modifier genes may play a role in disease manifestation and severity. In this study we prospectively assessed two families with known BMPR2 or ENG mutations clinically and genetically and screened for a second mutation in the BMPR2 promoter region. Methods: We investigated the BMPR2 promoter region by direct sequencing in two index-patients with invasively confirmed diagnosis of HPAH, carrying a mutation in the BMPR2 and ENG gene, respectively. Sixteen family members have been assessed clinically by non-invasive methods and genetically by direct sequencing. Results: In both index patients with a primary BMPR2 deletion (exon 2 and 3) and Endoglin missense variant (c.1633G>A, p.(G545S)), respectively, we detected a second mutation (c.-669G>A) in the promoter region of the BMPR2 gene. The index patients with 2 mutations/variants were clinically severely affected at early age, whereas further family members with only one mutation had no manifest HPAH. Conclusion: The finding of this study supports the hypothesis that additional mutations may lead to an early and severe manifestation of HPAH. This study shows for the first time that in the regulatory region of the BMPR2 gene the promoter may be important for disease penetrance. Further studies are needed to assess the incidence and clinical relevance of mutations of the BMPR2 promoter region in a larger patient cohort. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the minimal set of genetic alterations required for the development of a very low risk clinically symptomatic gastro-intestinal stromal tumour within the stomach wall. We studied the genome of a very low-risk gastric gastro-intestinal stromal tumour by whole-genome sequencing, comparative genomic hybridisation and methylation profiling. The studied tumour harboured two typical genomic lesions: loss of the long arm of chromosome 14 and an activating mutation in exon 11 of KIT. Besides these genetic lesions, only two point mutations that may affect tumour progression were identified: A frame-shift deletion in RNF146 and a missense mutation in a zinc finger of ZNF407. Whilst the frameshift deletion in RNF146 seemed to be restricted to this particular tumour, a similar yet germline mutation in ZNF407 was found in a panel of 52 gastro-intestinal stromal tumours from different anatomical sites and different categories. Germline polymorphisms in the mitotic checkpoint proteins Aurora kinase A and BUB1 kinase B may have furthered tumour growth. The epigenetic profile of the tumour matches that of other KIT-mutant tumours. We have identified mutations in three genes and loss of the long arm of chromosome 14 as the so far minimal set of genetic abnormalities sufficient for the development of a very low risk clinically symptomatic gastric stromal tumour. [ABSTRACT FROM AUTHOR]

SATB2, a gene encoding a highly conserved DNA-binding protein, is known to have an important role in craniofacial and neuronal development. Only a few patients with SATB2 variants have been described so far. Recently, Döcker et al provided a summary of these patients and delineated the SAS (SATB2-associated syndrome). We here report on a girl with intellectual disability, nearly absent speech and suspected hypodontia who was shown to carry an intragenic SATB2 tandem duplication hypothesized to lead to haploinsufficiency of SATB2. Preliminary information on this patient had already been included in the article by Döcker et al. We want to give a detailed description of the patient's phenotype and genotype, providing further insight into the spectrum of the molecular mechanisms leading to SAS. [ABSTRACT FROM AUTHOR]

Background Sox6 is a transcription factor that is crucial for the differentiation and development of cortical interneurons and dopaminergic neurons of the substantia nigra pars compact. Loss-of-function mutations might thus result in complex paroxysmal diseases such as epilepsy syndromes or movement disorders. Patient We present a 15-year-old boy with delayed speech development and attention deficit hyperactivity disorder who presented with a rapid-onset generalized dopa-responsive dystonia. Results Neurological examination revealed generalized dystonic and frequent athetoid movements of the arms, trunk, and neck. Gait was severely impaired secondary to frequent dystonic postures. Both a resting tremor and action tremors were observed in both hands. Speech was dysarthric but language comprehension was unimpaired. Testing for saccadic dysfunction revealed hypometric horizontal and vertical saccades. Physical examination was otherwise significant for a pectus carinatum and splenomegaly. Laboratory studies, brain magnetic resonance imaging, and electroencephalography were unremarkable. Treatment with levodopa/carbidopa led to a complete and sustained remission of neurological symptoms. Genetic testing revealed a mono-allelic de novo 84-kb deletion on chromosome 11p15.2 encompassing exons 14-16 of the SOX6 gene (chr11: 15944880-16029095, NCBI 37/hg19). Conclusions This is the first report of a dopa-responsive movement disorder associated with SOX6 disruption. SOX6 mutations should be considered in the differential diagnosis of unexplained dopa-responsive dystonia syndromes. [ABSTRACT FROM AUTHOR]

Background: Transthyretin-related amyloidosis (ATTR) is characterized by a wide heterogeneity of genotypes and predominantly neurological and cardiac phenotypes. This study aims to characterize a cohort of patients with the rare transthyretin ( TTR) Val20Ile (p.TTRVal40Ile) variant. Methods and results: This study comprises a single-center cohort of 59 individuals subsequently evaluated for TTRVal20Ile variant due to clinical ( n = 13) or predictive ( n = 46) reasons. All patients were mainly related to Wagshurst, a small village in the South of Germany. Clinical assessment was performed by neurological evaluation, echocardiography, electrocardiography, cardiac biomarkers, cardiac MRI ( n = 13), and 99mTc-DPD scintigraphy ( n = 16). The rare TTRVal20Ile variant was found in 41 patients; evidence of cardiac amyloidosis was present in 22 patients. Evidence of pulmonary involvement was obtained by 99mTc-DPD scintigraphy in eight patients. No further organ involvement was observed in any of the patients carrying TTRVal20Ile variant. Correlation of inter-ventricular septum thickness as well as decrease of left ventricular longitudinal contractility with age was observed. Moreover, thickness of inter-ventricular septum correlated with NT-proBNP plasma levels and decrease in mitral annular plane systolic excursion. Cardiac manifestation started during the early sixth life decade indicated by higher left ventricular septum thickness and NT-proBNP plasma levels as compared to patients in fifth decade of life. All patients of the seventh and eighth life decade ( n = 10) presented with cardiac amyloidosis. During median follow-up of 26 (0-108) months, eight patients underwent heart transplantation with 1-year mortality rate of 25%. Conclusions: This large cohort of individuals carrying the TTRVal20Ile mutation reveals a predominantly cardiac phenotype with high penetrance and late onset of symptoms. Cardiac manifestation progressed to end-stage heart failure within a few years, finally requiring heart transplantation with promising long-term survival rates. [ABSTRACT FROM AUTHOR]

Familial amyloid polyneuropathy (FAP) is a progressive systemic autosomal dominant disease caused by pathogenic mutations in the transthyretin ( TTR) gene. We studied clinical, electrophysiological, histopathological, and genetic characteristics in 15 (13 late-onset and two early-onset) patients belonging to 14 families with polyneuropathy and mutations in TTR. In comparison, we analysed the features of nine unrelated patients with an idiopathic polyneuropathy, in whom TTR mutations have been excluded. Disease occurrence was familial in 36 % of the patients with TTR-associated polyneuropathy and the late-onset type was observed in 86 % (mean age at onset 65.5 years). Clinically, all late-onset TTR-mutant patients presented with distal weakness, pansensory loss, absence of deep tendon reflexes, and sensorimotor hand involvement. Afferent-ataxic gait was present in 92 % leading to wheelchair dependence in 60 % after a mean duration of 4.6 years. Autonomic involvement was observed in 60 %, and ankle edema in 92 %. The sensorimotor polyneuropathy was from an axonal type in 82 %, demyelinating or mixed type in 9 % each. Compared to the TTR-unmutated idiopathic polyneuropathy patients, we identified rapid progression, early ambulatory loss, and autonomic disturbances, associated with a severe polyneuropathy as red flags for TTR–FAP. In 18 % of the late-onset TTR-FAP patients, no amyloid was found in nerve biopsies. Further diagnostic pitfalls were unspecific electrophysiology, and coincident diabetes mellitus (23 %) or monoclonal gammopathy (7 %). We conclude that a rapid disease course, severely ataxic gait, hand involvement, and autonomic dysfunction are diagnostic hallmarks of late-onset TTR–FAP. Genetic analysis should be performed even when amyloid deposits are lacking or when polyneuropathy-causing comorbidities are concomitant. [ABSTRACT FROM AUTHOR]

Introduction Familial amyloid polyneuropathy ( FAP) is the most common subtype of hereditary amyloidosis. The amyloid protein transthyretin deposits as rigid amyloid fibers in the extracellular matrix of various tissues including peripheral nerves, heart, and gastrointestinal tract. As the mutated amyloid protein is mainly produced in the liver, one form of treatment to halt the progression of disease is liver transplantation ( LT). This study was performed to identify risk factors for decreased overall survival. Methods Clinical data of 21 transplant patients who underwent LT for FAP between 1996 and 2011 were analyzed retrospectively. Results The majority of patients had cardiac symptoms (76%), gastrointestinal symptoms (71%), or peripheral polyneuropathy (71%). A conventional operating technique was performed on 11 patients using end-to-end caval anastomoses, while the modified piggyback technique by Belghiti was performed on 10 patients. Overall survival analysis revealed a one-yr survival rate of 74.3% and three- and five-yr survival rates of 60.0% and 52.5%, respectively. Pre-operative modified body mass index ( mBMI) <700 kg g/L m² and time interval between diagnosis and operation before LT resulted in significantly lower overall survival (p = 0.0137; p = 0.033). Conclusion The pre-operative nutritional status and time interval between diagnosis and operation before LT influence overall survival after LT for hereditary amyloidosis. [ABSTRACT FROM AUTHOR]

Background: Aim of this prospective study was to compare clinical and genetic findings in children with idiopathic or heritable pulmonary arterial hypertension (I/HPAH) with children affected with congenital heart defects associated PAH (CHD-APAH). Methods: Prospectively included were 40 consecutive children with invasively diagnosed I/HPAH or CHD-APAH and 117 relatives. Assessment of family members, pedigree analysis and systematic screening for mutations in TGFß genes were performed. Results: Five mutations in the bone morphogenetic protein type II receptor (BMPR2) gene, 2 Activin A receptor type II-like kinase-1 (ACVRL1) mutations and one Endoglin (ENG) mutation were found in the 29 I/HPAH children. Two mutations in BMPR2 and one mutation in ACVRL1 and ENG, respectively, are described for the first time. In the 11 children with CHD-APAH one BMPR2 gene mutation and one Endoglin gene mutation were found. Clinical assessment of relatives revealed familial aggregation of the disease in 6 children with PAH (HPAH) and one CHD-APAH patient. Patients with mutations had a significantly lower PVR. Conclusion: Mutations in different TGFß genes occurred in 8/29 (27.6%) I/HPAH patients and in 2/11 (18.2%) CHD-APAH patients and may influence the clinical status of the disease. Therefore, genetic analysis in children with PAH, especially in those with I/HPAH, may be of clinical relevance and shows the complexity of the genetic background. [ABSTRACT FROM AUTHOR]

Background: Mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene can lead to idiopathic pulmonary arterial hypertension (IPAH). This study prospectively screened for BMPR2 mutations in a large cohort of PAH-patients and compared clinical features between BMPR2 mutation carriers and non-carriers.Methods: Patients have been assessed by right heart catheterization and genetic testing. In all patients a detailed family history and pedigree analysis have been obtained. We compared age at diagnosis and hemodynamic parameters between carriers and non-carriers of BMPR2 mutations. In non-carriers with familial aggregation of PAH further genes/gene regions as the BMPR2 promoter region, the ACVRL1, Endoglin, and SMAD8 genes have been analysed.Results: Of the 231 index patients 22 revealed a confirmed familial aggregation of the disease (HPAH), 209 patients had sporadic IPAH. In 49 patients (86.3% of patients with familial aggregation and 14.3% of sporadic IPAH) mutations of the BMPR2 gene have been identified. Twelve BMPR2 mutations and 3 unclassified sequence variants have not yet been described before. Mutation carriers were significantly younger at diagnosis than non-carriers (38.53 ± 12.38 vs. 45.78 ± 11.32 years, p < 0.001) and had a more severe hemodynamic compromise. No gene defects have been detected in 3 patients with HPAH.Conclusion: This study identified in a large prospectively assessed cohort of PAH- patients new BMPR2 mutations, which have not been described before and confirmed previous findings that mutation carriers are younger at diagnosis with a more severe hemodynamic compromise. Thus, screening for BMPR2 mutations may be clinically useful. [ABSTRACT FROM AUTHOR]

Ornithine transcarbamylase deficiency (OTCD) is the most common malfunction of ureagenesis. The case of a male newborn who died at the age of 2 days for clinically unclear reasons is presented. The post-mortem routine and esoteric testing methods that finally led to the diagnosis of a fatal case of OTCD are outlined here. [ABSTRACT FROM AUTHOR]

The article presents two cases that promote the need to assign the parental alleles, particularly in the context of prenatal diagnosis of cystic fibrosis (CF) or carrier testing. The cases involve a newborn Turkish girl and an almost 2-year-old girl, both were diagnosed with CF. Moreover, the authors conclude that commercial CFTR kits cannot guarantee correct results for all possible mutations and suggests that CFTR genotypes of CF patients should always be confirmed by testing the parents.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease which is often caused by recurrent emboli. These are also frequently found in patients with myeloproliferative diseases. While myeloproliferative diseases can be caused by gene defects, the genetic predisposition to CTEPH is largely unexplored. Therefore, the objective of this study was to analyse these genes and further genes involved in pulmonary hypertension in CTEPH patients. A systematic screening was conducted for pathogenic variants using a gene panel based on next generation sequencing. CTEPH was diagnosed according to current guidelines. In this study, out of 40 CTEPH patients 4 (10%) carried pathogenic variants. One patient had a nonsense variant (c.2071A>T p.Lys691*) in the BMPR2 gene and three further patients carried the same pathogenic variant (missense variant, c.1849G>T p.Val617Phe) in the Janus kinase 2 (JAK2) gene. The latter led to a myeloproliferative disease in each patient. The prevalence of this JAK2 variant was significantly higher than expected (p < 0.0001). CTEPH patients may have a genetic predisposition more often than previously thought. The predisposition for myeloproliferative diseases could be an additional risk factor for CTEPH development. Thus, clinical screening for myeloproliferative diseases and genetic testing may be considered also for CTEPH patients. [ABSTRACT FROM AUTHOR]

Background: Fragile-X-Mental-Retardation-1- (FMR1)-gene is supposed to be a key gene for ovarian reserve and folliculogenesis. It contains in its 5'-UTR a triplet-base-repeat (CGG), that varies between 26 and 34 in general population. CGG-repeat-lengths with 55–200 repeats (pre-mutation = PM) show instable heredity with a tendency to increase and are associated with premature-ovarian-insufficiency or failure (POI/POF) in about 20%. FMR1-mRNA-expression in leucocytes and granulosa cells (GCs) increases with CGG-repeat-length in PM-carriers, but variable FMR1-expression profiles were also described in women with POI without PM-FMR1 repeat-length. Additionally, associations between low numbers of retrieved oocytes and elevated FMR1-expression levels have been shown in GCs of females with mid-range PM-CGG-repeats without POI. Effects of FMR1-repeat-lengths-deviations (n < 26 or n > 34) below the PM range (n < 55) on ovarian reserve and response to ovarian stimulation remain controversial. Methods: We enrolled 229 women undergoing controlled ovarian hyperstimulation for IVF/ICSI-treatment and devided them in three ovarian-response-subgroups: Poor responder (POR) after Bologna Criteria, polycystic ovary syndrome (PCO) after Rotterdam Criteria, or normal responder (NOR, control group). Subjects were subdivided into six genotypes according to their be-allelic CGG-repeat length. FMR1-CGG-repeat-length was determined using ALF-express-DNA-sequencer or ABI 3100/3130 × 1-sequencer. mRNA was extracted from GCs after follicular aspiration and quantitative FMR1-expression was determined using specific TaqMan-Assay and applying the ΔΔCT method. Kruskall-Wallis-Test or ANOVA were used for simple comparison between ovarian reserve (NOR, POR or PCO) and CGG-subgroups or cohort demographic data. All statistical analysis were performed with SPSS and statistical significance was set at p ≤ 0.05. Results: A statistically significant increase in FMR1-mRNA-expression-levels was detected in GCs of PORs with heterozygous normal/low-CGG-repeat-length compared with other genotypes (p = 0.044). Conclusion: Female ovarian response may be negatively affected by low CGG-alleles during stimulation. In addition, due to a low-allele-effect, folliculogenesis may be impaired already prior to stimulation leading to diminished ovarian reserve and poor ovarian response. A better understanding of FMR1 expression-regulation in GCs may help to elucidate pathomechanisms of folliculogenesis disorders and to develop risk-adjusted treatments for IVF/ICSI-therapy. Herewith FMR1-genotyping potentially provides a better estimatation of treatment outcome and allows the optimal adaptation of stimulation protocols in future. [ABSTRACT FROM AUTHOR]