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Summary: Congenital adrenal hyperplasia (CAH) is one of the most common inherited rare endocrine disorders. This case report presents two female siblings with delayed diagnosis of non-classical CAH 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2D/HSD3B2) despite early hospital admission and apparent CAH manifestations such as infections, hirsutism, menstrual disturbances, and PCOS phenotype. Initially, sister 1 was misdiagnosed with PCOS and then 11-hydroxylase deficiency (CYP11B1), based on ultrasound, biochemical findings, and negative genetic testing for 21-hydroxylase deficiency (CYP21A2). Additional diagnostic workup was performed when sister 2also presented with symptoms of androgen excess. Genetic testing for CAH/steroid disorders finally revealed that both siblings were compound heterozygous for two variants in the HSD3B2 gene: a frameshift variant, c.558dup, p.(Thr187Hisfs*17) and a novel missense variant, c.65T>C, p.(Leu22Ser). A Synacthen test showed an insufficient cortisol increase. In vitro studies of the variants in a cell model revealed loss of function for the p.(Thr187Hisfs*17) and partial activity for p.(Leu22Ser) confirming non-classic CAH. Overlapping symptomatology and lack of specialized knowledge on steroid biosynthesis and associated rarest forms of CAH may explain the delayed diagnosis. However, with newer diagnostic methods comprising a less biased approach, very rare forms of non-classical CAH may no longer be overlooked in the future., Learning Points: Non-classic 3βHSD2 is likely underdiagnosed. Late diagnosis of mild non-classic 3βHSD2 does occur and one should be aware of this diagnosis. Early diagnosis of NCCAH may prevent many consequences such as severe hirsutism, prolonged menstrual irregularities, infertility, or even adrenal crisis with severe infections. Comprehensive steroid profiling and genetic testing should be used earlier, especially when in doubt about a diagnosis.

Palmoplantar keratoderma (PPK) is a heterogeneous group of rare skin diseases characterized by hyperkeratosis on the palms or soles. The subtype isolated punctate PPK is caused by heterozygous variants in AAGAB. We investigated if the variant AAGAB c.370C>T, p.Arg124Ter in patients with punctate PPK in the Region of Southern Denmark represented a founder variant and estimated the age to the most recent common ancestor. We performed haplotype analysis on samples from 20 patients diagnosed with punctate PPK and the AAGAB c.370C>T, p.Arg124Ter variant. Using the Gamma Method, we calculated the years to the most recent common ancestor. We also explored the presence of the variant in other populations through literature and databases (HGMD, ClinVar, and gnomAD). Our analysis revealed a shared haplotype of 3.0 Mb, suggesting shared ancestry. The ancestral haplogroup was estimated to an age of 12.1 generations (CI: 4.9-20.3) equivalent to approximately 339 years (CI: 137-568). This study confirms that the frequently observed variant AAGAB c.370C>T, p.Arg124Ter in punctate PPK among patients in the Region of Southern Denmark is caused by a founder variant. We recommend testing for the variant as initial screening in our region and potentially for all Danish patients presenting with punctate PPK., (© 2024 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Background: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome., Methods: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants., Results: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving., Conclusions: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing., (© 2023. Crown.)

Introduction: The risk of cancer in patients with solitary colorectal juvenile polyps (JPs) is poorly investigated and several studies have reported polyps with dysplastic and adenomatous alterations. We aimed to investigate the long-term risk of cancer and mortality in these patients by merging data from national registers and comparing them to a matched control cohort., Materials and Methods: Patients with a solitary JP were identified in The Danish National Pathology Register and Data Bank (DNPR). The included patients were matched on sex, age, and place of birth with 50 controls. The groups were then analyzed for risk of cancer using the Danish Cancer Registry and mortality using the Danish Cause of Death Registry., Results: We identified 1781 patients with solitary JPs and matched them with 83,713 controls. The mean follow-up time was 7.65 years for cases and 7.36 years for controls. The risk of cancer, including colorectal cancer, did not differ for the two groups and when adjusting for sex and year of birth, the hazard ratio (HR) was 1.15 (confidence interval [CI] 95% 0.94-1.41, p = 0.162). There was no increased risk of death (HR: 1.07, CI 95% 0.88-1.30, p = 0.486). The risk did not differ for different age groups or sex., Conclusion: There is no increased risk of cancer or mortality for patients with solitary colorectal JPs. Thus, endoscopic follow-up may be safely omitted in these patients., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Competing Interests: John Gásdal Karstensen is a consultant in SNIPR BIOME. Otherwise the authors have noting to declare.

Background: An association between punctate palmoplantar keratoderma type 1 (PPPK1) and malignancy has been proposed for decades. Some authors suggest that individuals with PPPK1 should undergo screening for various types of malignancies while others caution that an association is not well-established. In this systematic review, we summarized and evaluated the current evidence for a possible association between PPPK1 and malignancy., Methods: The review was conducted along PRISMA guidelines. The search used Embase, MEDLINE, Scopus, and the Human Gene Mutation Database up to March 2022. All studies reporting on individuals with the diagnosis of PPPK1 with or without history of malignancy were included. Two authors screened for eligible studies, extracted predefined data, and performed a quality assessment., Results: Of 773 studies identified, 45 were included. Most studies were reports on single families (24 of 45 studies) or multiple families (10 of 45 studies). The number of index cases with PPPK1 across all included studies was 280, and when family members reported with PPPK1 were added, a total of 817 individuals were identified. Overall, 23 studies reported on individuals with PPPK1 with a history of malignancy, whereas 22 studies reported on individuals with PPPK1 without a history of malignancy. Although the extracted data were not considered to be of sufficient quality to synthesize and answer our research question, the review did not confirm an association between PPPK1 and malignancy., Conclusion: This review shows that there is a lack of well-designed studies on this topic to conclude whether individuals with PPPK1 have an increased risk of malignancy. Based on the present literature, however, we could not confirm an association between PPPK1 and malignancy and find it highly questionable if patients with PPPK1 should be offered surveillance for malignancies., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)

Objective: This study aimed to assess the diagnostic yield of prenatal genetic testing using trio whole exome sequencing (WES) and trio whole genome sequencing (WGS) in pregnancies with fetal anomalies by comparing the results with conventional chromosomal microarray (CMA) analysis., Methods: A total of 40 pregnancies with fetal anomalies or increased nuchal translucency (NT ≥ 5 mm) were included between the 12th and 21st week of gestation. Trio WES/WGS and CMA were performed in all cases., Results: The trio WES/WGS analysis increased the diagnostic yield by 25% in cases with negative CMA results. Furthermore, all six chromosomal aberrations identified by CMA were independently detected by WES/WGS analysis. In total, 16 out of 40 cases obtained a genetic sequence variant, copy number variant, or aneuploidy explaining the phenotype, resulting in an overall WES/WGS diagnostic yield of 40%. WES analysis provided a more reliable identification of mosaic sequence variants than WGS because of its higher sequencing depth., Conclusions: Prenatal WES/WGS proved to be powerful diagnostic tools for fetal anomalies, surpassing the diagnostic yield of CMA. They have the potential to serve as standalone methods for prenatal diagnosis. The study highlighted the limitations of WGS in accurately detecting mosaic variants, which is particularly relevant when analyzing chorionic villus samples., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Peutz-Jeghers syndrome (PJS) is an autosomal dominant hereditary polyposis syndrome causing increased morbidity and mortality due to complications of polyposis and the development of cancer. STK11 is the only gene known to be associated with PJS, although in 10%-15% of patients fulfilling the diagnostic criteria no pathogenic variant (PV) is identified. The primary aim of this study was to identify the genetic etiology in all known PJS patients in Denmark and to estimate the risk of cancer, effect of surveillance and overall survival. We identified 56 patients (2-83 years old) with PJS. The detection rate of PVs was 96%, including three cases of mosaicism (6%). In two patients a variant was not detected. At the age of 40 years, the probabilities of cancer and death were 21% and 16%, respectively; at the age of 70 years these probabilities were 71% and 69%. Most cases of cancer (92%) were identified between the scheduled examinations in the surveillance program. These observations emphasize that PJS should be regarded as a general cancer predisposition syndrome, where improvement of clinical care is needed., (© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

A 1-year-old girl presented with porcelain white fingernails, accidentally discovered when she was referred for an infantile hemangioma consultation. The family reported that the nails had been milky white since birth and her father had similar white finger and toenails. The father remembered that additional family members on his side of the family presented with white nails; however, he could not provide exact information about the number of other relatives affected by this nail abnormality. The girl and her father were the only available family members with white nails presented for this study (Figure 1). The girl presented with leukonychia totalis on all fingernails only, while the father had this abnormality on all finger and toenails (Figure 2). We were not aware of any association with other diseases or features in this family, except hemangioma in the girl. ( SKINmed . 2023;21:44-46).

Background: Since the first description of a BRWD3-associated nonsydromic intellectual disability (ID) disorder in 2007, 21 additional families have been reported in the literature., Methods: Using exome sequencing (ES) and international data sharing, we identified 14 additional unrelated individuals with pathogenic BRWD3 variants (12 males and 2 females, including one with skewed X-inactivation). We reviewed the 31 previously published cases in the literature with clinical data available, and describe the collective phenotypes of 43 males and 2 females, with 33 different BRWD3 variants., Results: The most common features in males (excluding one patient with a mosaic variant) included ID (39/39 males), speech delay (24/25 males), postnatal macrocephaly (28/35 males) with prominent forehead (18/25 males) and large ears (14/26 males), and obesity (12/27 males). Both females presented with macrocephaly, speech delay, and epilepsy, while epilepsy was only observed in 4/41 males. Among the 28 variants with available segregation reported, 19 were inherited from unaffected mothers and 9 were de novo., Conclusion: This study demonstrates that the BRWD3-related phenotypes are largely non-specific, leading to difficulty in clinical recognition of this disorder. A genotype-first approach, however, allows for the more efficient diagnosis of the BRWD3-related nonsyndromic ID. The refined clinical features presented here may provide additional diagnostic assistance for reverse phenotyping efforts., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Masson SAS.)

von Hippel Lindau disease (vHL) is caused by a hereditary predisposition to multiple neoplasms, especially hemangioblastomas in the retina and CNS, renal cell carcinomas (RCC), pheochromocytomas, neuroendocrine pancreatic tumours (PNET) and endolymphatic sac tumours. Evidence based approaches are needed to ensure an optimal clinical care, while minimizing the burden for the patients and their families. This guideline is based on evidence from the international vHL literature and extensive research of geno- and phenotypic characteristics, disease progression and surveillance effect in the national Danish vHL cohort. We included the views and preferences of the Danish vHL patients, ensured consensus among Danish experts and compared with international recommendations. RECOMMENDATIONS: vHL can be diagnosed on clinical criteria, only; however, in most cases the diagnosis can be supported by identification of a pathogenic or likely pathogenic variant in VHL. Surveillance should be initiated in childhood in persons with, or at risk of, vHL, and include regular examination of the retina, CNS, inner ear, kidneys, neuroendocrine glands, and pancreas. Treatment of vHL manifestations should be planned to optimize the chance of cure, without unnecessary sequelae. Most manifestations are currently treated by surgery. However, belzutifan, that targets HIF-2α was recently approved by the U.S. Food and Drug Administration (FDA) for adult patients with vHL-associated RCC, CNS hemangioblastomas, or PNETs, not requiring immediate surgery. Diagnostics, surveillance, and treatment of vHL can be undertaken successfully by experts collaborating in multidisciplinary teams. Systematic registration, collaboration with patient organisations, and research are fundamental for the continuous improvement of clinical care and optimization of outcome with minimal patient inconvenience., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease., Methods: Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher., Results: Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present., Conclusion: We established SRRM2 as a gene responsible for a rare neurodevelopmental disease., Competing Interests: Conflict of Interest This work was carried out within the framework of Nantes University Medical Center activity without additional funding. One patient was diagnosed in the context of work in a private company (AiLife Diagnostics, Pearland, Texas). The other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare genodermatosis characterized by cutaneous leiomyoma (CLM), uterine leiomyoma (ULM) and renal cell carcinoma (RCC). Five HLRCC patients are presented with a compiled database of published HLRCC cases to increase understanding of HLRCC. Furthermore, a surveillance program is suggested. Our review is based on a PubMed search which retrieved case reports and cohort studies published before November 2019. The search yielded 97 original papers with a total of 672 HLRCC patients., Results: CLMs were present in 474 patients (71.5%), developed at the mean age of 28 years. Five patients had cutaneous leiomyosarcomas. ULMs were present in 356 women (83%), while two had uterine leiomyosarcoma. ULMs were diagnosed at a mean age of 32 years, with the youngest diagnosed at age 17 years. The most common surgical treatment for ULMs was hysterectomy, performed at a mean age of 35 years, with the youngest patient being 19 years old. RCCs were present in 189 patients (34.9%), of which half had metastatic disease. The mean age of diagnosis was 36 years with the youngest patient diagnosed with RCC at the age of 11 years., Conclusion: We suggest a surveillance program for HLRCC including a dermatological examination once every 2 years, annual magnetic resonance imaging starting at the age of 10 years to monitor for early RCCs, annual gynecological examinations from the age of 15 years and counseling regarding risk of hysterectomy and family planning at the age of 18 years. CLMs are often the earliest manifestation of HLRCC, which is why recognizing these lesions, performing a biopsy, and making a prompt referral to genetic counseling is important in order to diagnose HLRCC early.

Background: Patients with germline variants in SMAD4 can present symptoms of both juvenile polyposis syndrome (JPS) and Hereditary Hemorrhagic Telangiectasia (HHT): JP-HHT syndrome. Next-Generation Sequencing (NGS) techniques disclose causative sequence variants in around 90% of HHT patients fulfilling the Curaçao criteria. Here we report a translocation event involving SMAD4 resulting in JP-HHT., Methods: A patient fulfilling the Curaçao criteria was analyzed for variants in ENG, ACVRL1, and SMAD4 using standard techniques. Whole-genome sequencing (WGS) using both short-read NGS technology and long-read Oxford Nanopore technology was performed to define the structural variant and exact breakpoints., Results: No pathogenic variant was detected in ENG, ACVRL1, or SMAD4 in DNA extracted from blood. Due to abortus habitualis, the proband´s daughter was submitted for chromosomal analysis, and a cytogenetically balanced chromosomal reciprocal translocation t(1;18)(p36.1;q21.1) was detected in the daughter and the patient. The balanced translocation segregated with both gastrointestinal cancer and HHT in the family. WGS provided the exact breakpoints of the reciprocal translocation proving disruption of the SMAD4 gene., Discussion: A disease-causing reciprocal translocation between chromosome 1 and 18 with a breakpoint in the SMAD4 locus co-segregated with JP-HHT in an extended family. This observation warrants further analysis for chromosomal rearrangements in individuals with clinical HHT or JP-HHT of unknown cause., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Alport syndrome is a progressive hereditary kidney disease clinically presenting with haematuria, proteinuria, and early onset end-stage renal disease, and often accompanied by hearing loss and ocular abnormalities. The inheritance is X-linked in the majority of families and caused by sequence variants in the COL4A5 gene encoding the α5-chain of type-IV collagen. The proportion of de novo COL4A5 sequence variants in X-linked Alport syndrome has been reported between 12 and 15% in previous studies., Methods: In the present study we have systematically investigated the mosaic status of asymptomatic parents of six patients with X-linked Alport syndrome using next-generation sequencing of DNA extracted from different tissues. The deleterious COL4A5 sequence variants in these patients were previously assumed to be de novo, based on Sanger sequencing of the parents., Results: A low-grade (1%) parental mosaicism was detected in only one out of six families (17%). In addition, in one out of six families (17%), we found that the mutational event probably occurred postzygotic., Conclusion: These findings highlight the importance of testing for mosaicism in unaffected parents of patients with sequence variants considered to be de novo, as it may have implications for the recurrence risk and thereby for the genetic counseling of the family., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Introduction: Familial adenomatous polyposis (FAP) is an autosomal dominant-inherited disease caused by germline variants in the APC gene. It is characterized by the development of hundreds to thousands of adenomatous polyps in colon and rectum. Recently, biallelic germline variants in the base excision repair (BER) gene: MUTYH have been identified in patients with attenuated FAP and/or negative APC result. It can be responsible for an autosomal recessive inherited colorectal cancer syndrome (MAP syndrome: MUTYH-associated polyposis)., Objective: The aim of this study was to evaluate germline variants of MUTYH gene in Tunisian patients with attenuated FAP., Methods: thirteen unrelated patients from Tunisia with attenuated FAP were screened for MUTYH germline variants. Direct sequencing was performed to identify point variants in this gene., Results: A Biallelic MUTYH germline variant were found in all patients and showed an attenuated polyposis phenotype almost of them without extra-colic manifestations: The known pathogenic frameshift variant c.1227&#95;1228dupGG (p. Glu410Glyfs) was found, in homozygous state, in 13 index patients., Conclusion: Patients with attenuated familial adenomatous polyposis (<=100) and no obvious vertical transmission of the disease should be considered for MUTYH gene testing., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case-control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case series have attempted to delineate a microdeletion syndrome with considerable phenotypic variability. The literature on this deletion is extensive and confusing, which is a challenge for genetic counselling. The aim of this study was to estimate the effect size of the 15q11.2 deletion and quantify its contribution to neurodevelopmental disorders., Methods: We performed meta-analyses on new and previously published case-control studies and used statistical models trained in unselected populations with cognitive assessments. We used new (n=241) and previously published (n=150) data from a clinically referred group of deletion carriers. 15q11.2 duplications (new n=179 and previously published n=35) were used as a neutral control variant., Results: The deletion decreases IQ by 4.3 points. The estimated ORs and respective frequencies in deletion carriers for intellectual disabilities, schizophrenia and epilepsy are 1.7 (3.4%), 1.5 (2%) and 3.1 (2.1%), respectively. There is no increased risk for heart malformations and autism. In the clinically referred group, the frequency and nature of symptoms in deletions are not different from those observed in carriers of the 15q11.2 duplication suggesting that most of the reported symptoms are due to ascertainment bias., Conclusions: We recommend that the deletion should be classified as 'pathogenic of mild effect size'. Since it explains only a small proportion of the phenotypic variance in carriers, it is not worth discussing in the developmental clinic or in a prenatal setting., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: Evaluation of clinical findings and audiological outcome after surgery in a Danish family with autosomal dominant facio-audio-symphalangism syndrome with stapes fixation, syndactyly and symphalangism., Methods: Retrospective report on eight affected family members in a Danish family. Clinical investigation included X-ray, audiology and in one case video-recorded surgery. Main outcome measure was audiologic results after stapedectomy. Sanger DNA sequencing of NOG was performed on peripheral blood., Results: Audiologic analysis showed that seven of eight affected family members had bilateral conductive hearing loss. Three patients were treated with stapedectomy, on one or both ears, due to fixation of stapes. All the affected members had syndactyly and symphalangism. A not previously reported mutation in the NOG gene (c.688&#95;699del, p.Cys230&#95;Cys232delins11) was found to segregate with the stapes fixation, syndactyly, and symphalangism. p.Cys230&#95;Cysdelins11 was classified as likely pathogenic according to guidelines from the American College of Medical Genetics and Genomics., Conclusion: The clinical presentation of the reported mutation corresponds with previous case reports of families with NOG mutation. In this family, surgery with stapedectomy had lasting effect without renewed fixation of the stapes in a follow up period of 18 months-38 years., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Pigmentary mosaicism is a term that describes varied patterns of pigmentation in the skin caused by genetic heterogeneity of the skin cells. In a substantial number of cases, pigmentary mosaicism is observed alongside extracutaneous abnormalities typically involving the central nervous system and the musculoskeletal system. We have compiled information on previous cases of pigmentary mosaicism aiming to optimize the handling of patients with this condition. Our study is based on a database search in PubMed containing papers written in English, published between January 1985 and April 2017. The search yielded 174 relevant and original articles, detailing a total number of 651 patients., Results: Forty-three percent of the patients exhibited hyperpigmentation, 50% exhibited hypopigmentation, and 7% exhibited a combination of hyperpigmentation and hypopigmentation. Fifty-six percent exhibited extracutaneous manifestations. The presence of extracutaneous manifestations in each subgroup varied: 32% in patients with hyperpigmentation, 73% in patients with hypopigmentation, and 83% in patients with combined hyperpigmentation and hypopigmentation. Cytogenetic analyses were performed in 40% of the patients: peripheral blood lymphocytes were analysed in 48%, skin fibroblasts in 5%, and both analyses were performed in 40%. In the remaining 7% the analysed cell type was not specified. Forty-two percent of the tested patients exhibited an abnormal karyotype; 84% of those presented a mosaic state and 16% presented a non-mosaic structural or numerical abnormality. In patients with extracutaneous manifestations, 43% of the cytogenetically tested patients exhibited an abnormal karyotype. In patients without extracutaneous manifestations, 32% of the cytogenetically tested patients exhibited an abnormal karyotype., Conclusion: We recommend a uniform parlance when describing the clinical picture of pigmentary mosaicism. Based on the results found in this review, we recommend that patients with pigmentary mosaicism undergo physical examination, highlighting with Wood's light, and karyotyping from peripheral blood lymphocytes and skin fibroblasts. It is important that both patients with and without extracutaneous manifestations are tested cytogenetically, as the frequency of abnormal karyotype in the two groups seems comparable. According to the results only a minor part of patients, especially those without extracutaneous manifestations, are tested today reflecting a need for change in clinical practice.

Using trio whole-exome sequencing, we have identified de novo heterozygous pathogenic variants in GRIA4 in five unrelated individuals with intellectual disability and other symptoms. GRIA4 encodes an AMPA receptor subunit known as GluR4, which is found on excitatory glutamatergic synapses and is important for learning and memory. Four of the variants are located in the highly conserved SYTANLAAF motif in the transmembrane protein M3, and the fifth is in an extra-cellular domain. Molecular modeling of the altered protein showed that three of the variants in the SYTANLAAF motif orient toward the center of the pore region and most likely lead to disturbance of the gating mechanism. The fourth variant in the SYTANLAAF motif most likely results in reduced permeability. The variant in the extracellular domain potentially interferes with the binding between the monomers. On the basis of clinical information and genetic results, and the fact that other subunits of the AMPA receptor have already been associated with neurodevelopmental disorders, we suggest that pathogenic de novo variants in GRIA4 lead to intellectual disability with or without seizures, gait abnormalities, problems of social behavior, and other variable features., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Pathogenic germline mutations in the folliculin (FLCN) tumor suppressor gene predispose to Birt-Hogg-Dubé (BHD) syndrome, a rare disease characterized by the development of cutaneous hamartomas (fibrofolliculomas), multiple lung cysts, spontaneous pneumothoraces and renal cell cancer. In this study, we report the identification of 13 variants and three polymorphisms in the FLCN gene in 143 Danish patients or families with suspected BHD syndrome. Functional mini-gene splicing analysis revealed that two intronic variants (c.1062+2T>G and c.1177-5&#95;1177-3del) introduced splicing aberrations. Eleven families exhibited the c.1062+2T>G mutation. Combined single nucleotide polymorphism array-haplotype analysis showed that these families share a 3-Mb genomic fragment containing the FLCN gene, revealing that the c.1062+2T>G mutation is a Danish founder mutation. On the basis of in silico prediction and functional splicing assays, we classify the 16 identified variants in the FLCN gene as follows: nine as pathogenic, one as likely pathogenic, three as likely benign and three as polymorphisms. In conclusion, the study describes the FLCN mutation spectrum in Danish BHD patients, and contributes to a better understanding of BHD syndrome and management of BHD patients.

Pathogenic germline mutations in ELN can be detected in patients with supravalvular aortic stenosis. The mutation might occur de novo or be inherited following an autosomal dominant pattern of inheritance. In this report we describe a three-generation family suffering from supravalvular aortic stenosis, various other arterial stenoses, sudden death, and intracranial aneurysms. A frameshift mutation in exon 12, not described before, was detected in the affected family members. This report emphasises the importance of family history, genetic counselling, and demonstrates the great variability in the phenotype within a single SVAS family., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1), or Taybi-Linder syndrome is characterized by distinctive skeletal dysplasia, severe intrauterine and postnatal growth retardation, microcephaly, dysmorphic features, and neurological malformations. It is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the RNU4ATAC gene resulting in impaired function of the minor spliceosome. Here, we present the first report on bone morphology, bone density and bone microstructure in two adult MOPD1 patients and applied radiographs, dual energy X-ray absorptiometry, high-resolution peripheral quantitative computed tomography and biochemical evaluation. The MOPD1 patients presented with short stature, low BMI but normal macroscopic bone configuration. Bone mineral density was low. Compared to Danish reference data, total bone area, cortical bone area, cortical thickness, total bone density, cortical bone density, trabecular bone density and trabecular bone volume per tissue volume (BV/TV) were all low. These findings may correlate to the short stature and low body weight of the MOPD1 patients. Our findings suggest that minor spliceosome malfunction may be associated with altered bone modelling., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Acromelic frontonasal dysostosis (AFND) is a distinctive and rare frontonasal malformation that presents in combination with brain and limb abnormalities. A single recurrent heterozygous missense substitution in ZSWIM6, encoding a protein of unknown function, was previously shown to underlie this disorder in four unrelated cases. Here we describe four additional individuals from three families, comprising two sporadic subjects (one of whom had no limb malformation) and a mildly affected female with a severely affected son. In the latter family we demonstrate parental mosaicism through deep sequencing of DNA isolated from a variety of tissues, which each contain different levels of mutation. This has important implications for genetic counselling., (© 2015 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: A subgroup of patients with hamartomatous polyps in the GI tract has a hereditary Hamartomatous Polyposis Syndrome with an increased risk of cancer. The distinction between patients with one or few polyps and patients with a syndrome can be difficult. A pathogenic germline mutation can be detected in a majority of HPS patients. This study investigates whether patients with one or few hamartomatous polyps could have a syndrome based on genetic screening of relevant genes., Methods: We designed a gene panel including 26 hamartomatous polyposis-associated genes. Using targeted Next Generation Sequencing, DNA samples from 77 patients with 84 hamartomatous polyps were sequenced. The detected germline variants were classified into pathogenicity classes., Results: We detected several germline variants, among them three in ENG, two in BMPR1A, one in PTEN, and one in SMAD4. Although some of the detected variants have been reported previously none could be definitely pathogenic or likely pathogenic., Conclusions: Our study points towards that genetic testing for the Hamartomatous Polyposis Syndromes in patients with one or few polyps does not improve diagnostics, however we illustrate that the clinical significance of genetic variants can be difficult to interpret. A family history of polyps, cancer, or extraintestinal findings or a minimum of 3-5 polyps seems to be relevant information to include before genetic testing.

Background: Juvenile polyps in the large bowel are rare but the most common type of polyp in children. The prevalence and incidence are unknown, and few studies exist on the occurrence in adults. They are considered not to harbor any malignant potential unless they are part of the hereditary juvenile polyposis syndrome., Objective: We aimed to study the demographics of juvenile polyps in Denmark in a 20-year period from 1995 to 2015 in both adults and children. This is the first report on the occurrence, anatomic localization, and reoccurrence of these polyps in a whole population., Design: Data from all of the patients who had been diagnosed with 1 or more juvenile polyp from January 1, 1995, until December 31, 2014, were obtained., Settings: The study was conducted based on patients registered in the nationwide pathological register in Denmark, the Danish Pathology Data Bank., Patients: We detected a total of 1772 patients who had 2108 juvenile polyps removed (male = 946; female = 826)., Main Outcome Measures: We noted the sex, age, number, reoccurrence, and localization of polyps., Results: Of the detected juvenile polyps ≈75% were detected in adults and ≈25% in children. Approximately 96% of the patients had a single juvenile polyp without reoccurrence, 1% fulfilled the diagnostic criteria for juvenile polyposis syndrome (more than 5 polyps), and 5% had multiple juvenile polyps (2-5 polyps). The incidence in the Danish population can be estimated to be between 1:45,000 and 1:65,000., Limitations: Miscoding or misclassification in the register cannot be ruled out. We only have data for the 20-year period, limiting the evaluation of reoccurrence, and no data for the endoscopic removal procedures., Conclusions: We conclude that juvenile polyps are rare, with the majority found in adults, and most often found as a single juvenile polyp. A subgroup of patients have juvenile polyposis syndrome, which requires follow-up.

Patients with germline mutations in SMAD4 can present symptoms of both juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT): the JP-HHT syndrome. The complete phenotypic picture of this syndrome is only just emerging. We describe the clinical characteristics of 14 patients with SMAD4-mutations. The study was a retrospective, register-based study. SMAD4 mutations carriers were identified through the Danish HHT-registry, the genetic laboratories - and the genetic departments in Denmark. The medical files from relevant departments were reviewed and symptoms of HHT, JPS, aortopathy and family history were noted. We detected 14 patients with SMAD4 mutations. All patients had polyps removed and 11 of 14 fulfilled the diagnostic criteria for JPS. Eight patients were screened for HHT-symptoms and seven of these fulfilled the Curaçao criteria. One patient had aortic root dilation. Our findings support that SMAD4 mutations carriers have symptoms of both HHT and JPS and that the frequency of PAVM and gastric involvement with polyps is higher than in patients with HHT or JPS not caused by a SMAD4 mutation. Out of eight patients screened for aortopathy, one had aortic root dilatation, highlighting the need for additional screening for aortopathy., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: In this paper, we aimed to collect genetic and medical information on all Danish patients with Peutz-Jeghers syndrome (PJS), in order to contribute to the knowledge of phenotype and genotype. Peutz-Jeghers syndrome is a hereditary syndrome characterized by multiple hamartomatous polyps in the GI tract, mucocutaneous pigmentations, and an increased risk of cancer in the GI tract and at extraintestinal sites. Over 90 % of patients harbour a pathogenic mutation in STK11., Methods: Based on the Danish Pathology Data Bank, the Danish National Patient Register, as well as information from relevant departments at Danish hospitals, we identified patients and collected clinical and genetic information., Results: We identified 43 patients of which 14 were deceased. The prevalence was estimated to be ∼1 in 195,000 individuals. The median age at first symptom was 27.5 with invagination of the small bowel as the most frequent presenting symptom. We noted 18 occurrences of cancer at various anatomical sites, including a case of thyroid cancer and penile cancer. Eight of the deceased patients had died of cancer. Eighteen different mutations in STK11 had been detected in 28 patients., Conclusion: This is the first comprehensive study of patients with Peutz-Jeghers syndrome in the Danish population identified from nationwide registers and databases. We have demonstrated that the expressivity of Peutz-Jeghers syndrome varies greatly among the patients, even within the same families, underlining the great phenotypic spectrum. Patients with PJS should be offered surveillance from childhood in order to prevent morbidity and reduce mortality.

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

Following the implementation of high-throughput sequencing legal and ethical issues are discussed intensively. The management of incidental findings (IFs) in a research setting have been investigated but there is a lack of literature concerning research participant's perspective. The aim of this study was to investigate whether research participants want disclosure of IFs and what kind of IFs they want to know about. One hundred and twenty-seven research participants in a study of gastrointestinal polyps were informed about whole-exome sequencing and the risk of IFs. They were asked to decide whether they (A) wanted disclosure of IFs no matter whether the variants were associated with a non-treatable or non-preventable condition, (B) wanted disclosure of variants associated with treatable or preventable conditions or (C) wanted no disclosure at all. Participants who wanted disclosure of all the IFs (A) accounted for the majority (n=78), 45 of the participants only wanted disclosure of variants, which could lead to surveillance or treatment (B) and 4 participants did not want IFs to be disclosed at all (C). The study showed that almost all research participants wanted disclosure of at least some types of IFs.

Noonan syndrome is part of the group of RASopathies caused by germ line mutations in genes involved in the RAS/MAPK pathway. There is substantial phenotypic overlap among the RASopathies. Diagnosis of Noonan syndrome is often based on clinical features including dysmorphic facial features, short stature and congenital heart disease. Rapid advances in sequencing technology have made molecular genetic analyses a helpful tool in diagnosing and distinguishing Noonan syndrome from other RASopathies.

Basal cell naevus syndrome (Gorlin-Goltz syndrome) is a rare, autosomal dominantly inherited condition with a wide range of developmental and multiple organ-related anomalies. Cardinal features include multiple basal cell carcinomas, jaw cysts, palmoplantar pits and calcification of the falx cerebri. Other important clinical features are skeletal abnormalities and facial dysmorphism including macrocephaly. Germ-line mutations are found in PTCH1. Management of the syndrome requires a multidisciplinary approach, and in this article management guidelines are reviewed and discussed.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities, and subdivided in TRPS I, caused by mutations in TRPS1, and TRPS II, caused by a contiguous gene deletion affecting (amongst others) TRPS1 and EXT1. We performed a collaborative international study to delineate phenotype, natural history, variability, and genotype-phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals. TRPS I was present in 85 individuals (22 missense mutations, 62 other mutations), TRPS II in 14, and in 5 it remained uncertain whether TRPS1 was partially or completely deleted. Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella. The facial manifestations in patients with TRPS I and TRPS II do not show a significant difference. In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened. Nails of fingers and toes are typically thin and dystrophic. The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses. Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally. Variability for all findings, also within a single family, can be marked. Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age. Intellectual disability is uncommon in TRPS I and, if present, usually mild. In TRPS II intellectual disability is present in most but not all, and again typically mild to moderate in severity. Missense mutations are located exclusively in exon 6 and 7 of TRPS1. Other mutations are located anywhere in exons 4-7. Whole gene deletions are common but have variable breakpoints. Most of the phenotype in patients with TRPS II is explained by the deletion of TRPS1 and EXT1, but haploinsufficiency of RAD21 is also likely to contribute. Genotype-phenotype studies showed that mutations located in exon 6 may have somewhat more pronounced facial characteristics and more marked shortening of hands and feet compared to mutations located elsewhere in TRPS1, but numbers are too small to allow firm conclusions., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Unlabelled: Hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, is predominantly caused by mutations in ENG and ACVRL1, which are part of the transforming growth factor beta (TGF-β) signaling pathway. HHT is characterized by the presence of mucocutaneous telangiectases and arteriovenous malformations in visceral organs, primarily the lungs, brain and liver. The most common symptom in HHT is epistaxis originating from nasal telangiectasia, which can be difficult to prevent and can lead to severe anemia. The clinical manifestations of HHT are extremely variable, even within family members, and the exact mechanism of how endoglin and ALK1 haploinsufficiency leads to HHT manifestations remains to be identified., Objectives: The purpose of this study was to detect significantly differentially regulated genes in HHT, and try to elucidate the pathways and regulatory mechanisms occurring in the affected tissue of HHT patients, in order to further characterize this disorder and hypothesize on how telangiectases develop. By microarray technology (Agilent G3 Human GE 8x60), we performed global gene expression profiling of mRNA transcripts from HHT nasal telangiectasial (n = 40) and non-telangiectasial (n = 40) tissue using a paired design. Comparing HHT telangiectasial and non-telangiectasial tissue, significantly differentially expressed genes were detected using a paired t-test. Gene set analysis was performed using GSA-SNP. In the group of ENG mutation carriers, we detected 67 differentially expressed mRNAs, of which 62 were down-regulated in the telangiectasial tissue. Gene set analysis identified the gene ontology (GO) terms vasculogenesis, TGF-β signaling, and Wnt signaling as differentially expressed in HHT1. Altered Wnt signaling might be related to HHT pathogenesis and a greater understanding of this may lead to the discovery of therapeutic targets in HHT., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ∼ 1%-2% of CdLS-like phenotypes., (© 2015 WILEY PERIODICALS, INC.)

Juvenile polyposis syndrome is an autosomal dominant polyposis syndrome. It is characterized by predisposition to multiple juvenile polyps in the gastrointestinal tract and is associated with an increased risk of colorectal and ventricular cancer. Patients and at risk family members should be offered surveillance. This article discusses clinical features and surveillance based on the current literature.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominantly inherited vascular disease characterized by the presence of mucocutaneous telangiectasia and visceral arteriovenous malformations (AVM). The clinical diagnosis of HHT is based on the Curaçao criteria. About 85% of HHT patients carry mutations in the ENG, ACVRL1 or SMAD4 genes. Here, we report on the genetic heterogeneity in the Danish national HHT population and address the prevalence of pulmonary arteriovenous malformations (PAVM). Probands of 107 apparently unrelated families received genetic testing, including sequencing and multiplex ligation-dependent probe amplification (MLPA) analyses of ENG, ACVRL1 and SMAD4. These 107 families included 320 patients confirmed to have HHT either clinically or genetically. In 89% of the probands (n=95), a mutation was identified. We detected 64 unique mutations of which 27 (41%) were novel. Large deletions were identified in ENG and ACVRL1. The prevalence of PAVM was 52.3% in patients with an ENG mutation and 12.9% in the ACVRL1 mutation carriers. We diagnosed 80% of the patients clinically, fulfilling the Curaçao criteria, and those remaining were diagnosed by genetic testing. It is discussed when to assign pathogenicity to missense and splice site mutations. The adding of an extra criterion to the Curaçao criteria is suggested., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)