Further Delineation of Ribose-5-phosphate Isomerase Deficiency: Report of a Third Case.

J Child Neurol. 2018 Aug 08;:883073818789316

Authors: Brooks SS, Anderson S, Bhise V, Botti C

Abstract
Ribose-5-phosphate isomerase deficiency, a disorder of the pentose phosphate shunt, was described in 1999. There are 2 previously reported cases of ribose-5-phosphate isomerase deficiency. Here, we describe the clinical course, diagnostic odyssey, and molecular findings in the third case of ribose-5-phosphate isomerase deficiency to further delineate the syndrome. Whole-exome sequencing demonstrated 2 mutations in the ribose-5-phosphate isomerase gene, RPIA, in a child with neonatal onset leukoencephalopathy and psychomotor delays. Urine polyols were elevated confirming deficiency of ribose-5-phosphate isomerase (RPI, EC. 5.3.1.6) and pathogenicity of the variants. Measurement of urine polyols should be considered in cases of early-onset white-matter disease.

PMID: 30088433 [PubMed - as supplied by publisher]

Association of modifiers and other genetic factors explain Marfan syndrome clinical variability.

Eur J Hum Genet. 2018 Aug 07;:

Authors: Aubart M, Gazal S, Arnaud P, Benarroch L, Gross MS, Buratti J, Boland A, Meyer V, Zouali H, Hanna N, Milleron O, Stheneur C, Bourgeron T, Desguerre I, Jacob MP, Gouya L, Génin E, Deleuze JF, Jondeau G, Boileau C

Abstract
Marfan syndrome (MFS) is a rare autosomal dominant connective tissue disorder related to variants in the FBN1 gene. Prognosis is related to aortic risk of dissection following aneurysm. MFS clinical variability is notable, for age of onset as well as severity and number of clinical manifestations. To identify genetic modifiers, we combined genome-wide approaches in 1070 clinically well-characterized FBN1 disease-causing variant carriers: (1) an FBN1 eQTL analysis in 80 fibroblasts of FBN1 stop variant carriers, (2) a linkage analysis, (3) a kinship matrix association study in 14 clinically concordant and discordant sib-pairs, (4) a genome-wide association study and (5) a whole exome sequencing in 98 extreme phenotype samples.Three genetic mechanisms of variability were found. A new genotype/phenotype correlation with an excess of loss-of-cysteine variants (P = 0.004) in severely affected subjects. A second pathogenic event in another thoracic aortic aneurysm gene or the COL4A1 gene (known to be involved in cerebral aneurysm) was found in nine individuals. A polygenic model involving at least nine modifier loci (named gMod-M1-9) was observed through cross-mapping of results. Notably, gMod-M2 which co-localizes with PRKG1, in which activating variants have already been described in thoracic aortic aneurysm, and gMod-M3 co-localized with a metalloprotease (proteins of extra-cellular matrix regulation) cluster. Our results represent a major advance in understanding the complex genetic architecture of MFS and provide the first steps toward prediction of clinical evolution.

PMID: 30087447 [PubMed - as supplied by publisher]

Germline heterozygous variants in genes associated with familial hemophagocytic lymphohistiocytosis as a cause of increased bleeding.

Platelets. 2018 Jan;29(1):56-64

Authors: Fager Ferrari M, Leinoe E, Rossing M, Norström E, Strandberg K, Steen Sejersen T, Qvortrup K, Zetterberg E

Abstract
Familial hemophagocytic lymphohistiocytosis (FHL) is caused by biallelic variants in genes regulating granule secretion in cytotoxic lymphocytes. In FHL3-5, the affected genes UNC13D, STX11 and STXBP2 have further been shown to regulate the secretion of platelet granules, giving rise to compromised platelet function. Therefore, we aimed to investigate platelet degranulation in patients heterozygous for variants in UNC13D, STX11 and STXBP2. During the work-up of patients referred to the Coagulation Unit, Skåne University Hospital, Malmö, Sweden and the Department of Hematology, Rigshospitalet, Copenhagen, Denmark due to bleeding tendencies, 12 patients harboring heterozygous variants in UNC13D, STX11 or STXBP2 were identified using targeted whole exome sequencing. Transmission electron microscopy (TEM) was used to assess the secretion of platelet dense granules following thrombin stimulation. Platelet degranulation, activation and aggregation were further assessed by flow cytometry (FC) and light transmission aggregometry (LTA) with lumi-aggregometry. In total, eight out of twelve (67%) patients showed impaired degranulation by at least one of the assays (TEM, FC and LTA). In the 12 patients, eight different heterozygous variants were identified. One variant was strongly associated with impaired degranulation, while four of the variants were associated with impaired granule secretion to a slightly lesser extent. One additional variant was found in six out of the twelve patients, and was associated with varying degrees of degranulation impairment. Accordingly, six out of the eight (75%) identified variants were associated with impaired platelet degranulation. Our results suggest that heterozygous variants in UNC13D, STX11 and STXBP2 are sufficient to cause platelet secretion defects resulting in increased bleeding.

PMID: 28399723 [PubMed - indexed for MEDLINE]

Familial Mediterranean fever in Chinese adult patients.

Rheumatology (Oxford). 2018 Aug 02;:

Authors: Wu D, Shen M, Zeng X

Abstract
Objectives: FMF is the most frequent monogenic auto-inflammatory disease worldwide. There have been hardly any cases reported in the Chinese population. We aimed to describe the first cohort of adult FMF patients in China.
Methods: We evaluated all the adult patients suffering from FMF referred to our centre from April 2015 through March 2017. Patients were diagnosed clinically according to the Tel Hashomer criteria. Whole exome sequencing was performed in each patient.
Results: A total of 11 adult patients were diagnosed as FMF in our centre. The mean age of onset was 29.4 years (s.d. 18.2). All patients were of Chinese Han ethnicity with no positive family history. All patients had intermittent febrile episodes. During attacks, seven patients had generalized abdominal pain, three experienced chest pain, four developed arthritis and none reported erysipelas-like skin changes. No patient had evidence of AA amyloidosis. Every patient carried at least one variant in the MEFV gene. All patients had good response to colchicine.
Conclusion: Our study is the first to suggest the presence of FMF in the Chinese adult population. The late onset, often atypical and mild clinical manifestations and absence of AA amyloidosis in our patients might be related to low-penetrance and heterozygous MEFV variants. Our results await to be confirmed on larger Chinese populations.

PMID: 30085313 [PubMed - as supplied by publisher]

Marked response of a hypermutated adrenocorticotropic hormone-secreting pituitary carcinoma to ipilimumab and nivolumab.

J Clin Endocrinol Metab. 2018 Aug 01;:

Authors: Lin AL, Jonsson P, Tabar V, Yang TJ, Cuaron J, Beal K, Cohen M, Postow M, Rosenblum M, Shia J, DeAngelis LM, Taylor BS, Young RJ, Geer EB

Abstract
Context: Pituitary carcinoma is a rare and aggressive malignancy with a poor prognosis and few effective treatment options.
Case: A 35-year-old woman presented with an aggressive adrenocorticotropic hormone-secreting pituitary adenoma that initially responded to concurrent temozolomide and capecitabine prior to metastasizing to the liver. Following treatment with ipilimumab and nivolumab, the tumor volume of the dominant liver metastasis reduced by 92%, while the recurrent intracranial disease regressed by 59%. Simultaneously, her plasma ACTH level decreased from 45,550 pg/ml to 66 pg/ml.
Molecular evaluation: Both prospective clinical sequencing with MSK-IMPACT and retrospective whole-exome sequencing were performed to characterize the molecular alterations in the chemotherapy-naïve pituitary adenoma and the temozolomide-resistant liver metastasis. The liver metastasis harbored a somatic mutational burden consistent with alkylator-induced hypermutation that was absent from the treatment-naïve tumor. Resistance to TMZ treatment, acquisition of new oncogenic drivers, and subsequent sensitivity to immunotherapy may be attributed to hypermutation.
Conclusion: Combination treatment with ipilimumab and nivolumab may be an effective treatment in pituitary carcinoma. Clinical sequencing of pituitary tumors that have relapsed following treatment with conventional chemotherapy may identify the development of therapy-induced somatic hypermutation, which may be associated with treatment response to immunotherapy.

PMID: 30085142 [PubMed - as supplied by publisher]

Whole exome sequencing revealed HKDC1 as a candidate gene associated with autosomal-recessive retinitis pigmentosa.

Hum Mol Genet. 2018 Jul 31;:

Authors: Zhang L, Sun Z, Zhao P, Huang L, Xu M, Yang Y, Chen X, Lu F, Zhang X, Wang H, Zhang S, Liu W, Jiang Z, Ma S, Chen R, Zhao C, Yang Z, Sui R, Zhu X

Abstract
Retinitis pigmentosa (RP) is an inheritable retina degenerative disease leading to blindness. Despite the identification of 70 genes associated with RP, the genetic cause of approximately 40% of RP patients remains to be elucidated. Whole exome sequencing was applied on the probands of a RP cohort of 68 unsolved cases to identify candidate genetic mutations. A homozygous missense variant (c.173C > T, p.T58 M) was found in HKDC1 in two unrelated families presenting late-onset retinal degeneration. This variant affects highly conserved amino acid residue and is very rare in several databases and absent in 4000 ethnic-matched controls. Mutant HKDC1 protein partially lost hexokinase activity. Hkdc1 is expressed in the mouse retina and localized to photoreceptor inner segments. To elucidate the in vivo roles of Hkdc1 in the retina, we generated Hkdc1 knockout mouse models using CRISPR/Cas9 technique. Two independent alleles were identified and backcrossed to C57BL/6 J for 6 generation. Absence of HKDC1 expression in the Hkdc1 knockout retina was confirmed by western blot and immunostaning using HKDC1 antibody. Hkdc1 knockout mice exhibited reduced scotopic ERG response and thinner outer nuclear layer, similar to some of the human patient phenotypes. Loss of Hkdc1 led to mislocalization of rhodopsin to the inner segments and cell bodies of rods in some regions in the retina. Taken together, our data demonstrated that HKDC1 is associated with autosomal recessively inherited RP.

PMID: 30085091 [PubMed - as supplied by publisher]

A putative human infertility allele of the meiotic recombinase DMC1 does not affect fertility in mice.

Hum Mol Genet. 2018 Aug 01;:

Authors: Tran TN, Schimenti JC

Abstract
Whole exome or genome sequencing is becoming routine in clinical situations for identifying mutations underlying presumed genetic causes of disease, including infertility. While this is a powerful approach for implicating polymorphisms or de novo mutations in genes plausibly related to the phenotype, a greater challenge is to definitively prove causality. This is a crucial requisite for treatment, especially for infertility, in which validation options are limited. In this study, we created a mouse model of a putative infertility allele, DMC1M200V. DMC1 encodes a RecA homolog essential for meiotic recombination and fertility in mice. This allele was originally implicated as being responsible for sterility of a homozygous African woman, a conclusion supported by subsequent biochemical analyses of the mutant protein and by studies of yeast with the orthologous amino acid change. Here, we found that Dmc1M200V/M200V male and female mice are fully fertile and do not exhibit any gonadal abnormalities. Detailed immunocytological analysis of meiosis revealed no defects suggestive of compromised fertility. This study serves as a cautionary tale for making conclusions about consequences of genetic variants, especially with respect to infertility, and emphasizes the importance of conducting relevant biological assays for making accurate diagnoses in the era of genomic medicine.

PMID: 30085085 [PubMed - as supplied by publisher]

The epigenomic landscape of pituitary adenomas reveals specific alterations and differentiates among acromegaly, Cushing's disease and endocrine-inactive subtypes.

Clin Cancer Res. 2018 Jul 03;:

Authors: Salomon MP, Wang X, Marzese D, Hsu SC, Nelson N, Zhang X, Matsuba C, Takasumi Y, Ballesteros-Merino C, Fox BA, Barkhoudarian G, Kelly DF, Hoon DS

Abstract
Purpose Pituitary adenomas (PAs) are one of the most common benign neoplasms of the central nervous system. Although emerging evidence suggests roles for both genetic and epigenetic factors in tumorigenesis, the degree to which these factors contribute to disease remains poorly understood. Experimental Design A multi-platform analysis was performed to identify the genomic and epigenomic underpinnings of disease among the three major subtypes of surgically-resected PAs in 48 patients: growth hormone (GH)-secreting (n=17), adrenocorticotropic hormone (ACTH)-secreting (n=13, including 3 silent-ACTH adenomas), and endocrine-inactive (n=18). Whole-exome sequencing was used to profile the somatic mutational landscape, whole-transcriptome sequencing was used to identify disease specific patterns of gene expression, and array-based DNA methylation profiling was used to examine genome-wide patterns of DNA methylation. Results Recurrent single nucleotide and small indel somatic mutations were infrequent among the three adenoma subtypes. However, somatic copy number alterations (SCNAs) were identified in all three PA subtypes. Methylation analysis revealed adenoma subtype-specific DNA methylation profiles, with GH-secreting adenomas being dominated by hypomethylated sites. Likewise, gene expression patterns revealed adenoma subtype-specific profiles. Integrating DNA methylation and gene expression data revealed that hypomethylation of promoter regions are related with increased expression of GH1 and SSTR5 genes in GH-secreting adenomas and POMCgene in ACTH-secreting adenomas. Finally, multispectral IHC staining of immune-related proteins showed abundant expression of PD-L1among all three adenoma subtypes. Conclusions Taken together, these data stress the contribution of epigenomic alterations to disease specific etiology among adenoma subtypes and highlight potential targets for future immunotherapy-based treatments.

PMID: 30084836 [PubMed - as supplied by publisher]

An update on diagnostic options and considerations in limb girdle dystrophies.

Expert Rev Neurother. 2018 Aug 07;:

Authors: Angelini C, Giaretta L, Marozzo R

Abstract
INTRODUCTION: Limb Girdle Muscular Dystrophies (LGMD) encompasses a clinically heterogeneous group of rare, genetic progressive muscle disorders presenting with weakness and atrophy of predominant pelvic and shoulder muscles. The spectrum of disease severity ranges from severe childhood-onset muscular dystrophy to adult-onset dystrophy. Areas covered: The review presents an update of the clinical phenotypes and diagnostic options for LGMD including both dominant and recessive LGMD and consider their differential clinical and histopathological features. An overview of most common phenotypes and of possible complications is given. The management of the main clinical respiratory, cardiac and central nervous system complications are covered. The instrumental, muscle imaging and laboratory exams to assess and reach diagnosis are described. The use of recent genetic techniques such as Next Generation Sequencing (NGS), whole exome sequencing compared to other techniques (e.g. DNA sequencing, protein analysis) is covered. Currently available drugs or gene therapy and rehabilitation management are focused on. Expert Commentary: Many LGMD cases, which for a long time previously remained without a molecular diagnosis, can now be investigated by NGS. Gene mutation analysis is always required to obtain a certain molecular diagnosis, fundamental to select homogeneous group of patients for future pharmaceutical and gene trials.

PMID: 30084281 [PubMed - as supplied by publisher]

A recurrent homozygous NHLRC1 variant in siblings with Lafora disease.

Hum Genome Var. 2018;5:16

Authors: Araya N, Takahashi Y, Shimono M, Fukuda T, Kato M, Nakashima M, Matsumoto N, Saitsu H

Abstract
We report a case of two siblings with progressive myoclonus epilepsy whose parents were not consanguineous. Their clinical symptoms were typical of Lafora disease (LD), but skin biopsies revealed no Lafora bodies. Whole-exome sequencing identified a recurrent homozygous frameshift variant in the NHLRC1 gene in both siblings. The genetic analysis was useful for the diagnosis of LD, as neither consanguinity nor Lafora bodies were found.

PMID: 30083360 [PubMed]

Laying Anchor: Inserting Precision Health into a Public Health Genetics Policy Course.

Healthcare (Basel). 2018 Aug 03;6(3):

Authors: Modell SM, Citrin T, Kardia SLR

Abstract
The United States Precision Medicine Initiative (PMI) was announced by then President Barack Obama in January 2015. It is a national effort designed to take into account genetic, environmental, and lifestyle differences in the development of individually tailored forms of treatment and prevention. This goal was implemented in March 2015 with the formation of an advisory committee working group to provide a framework for the proposed national research cohort of one million or more participants. The working group further held a public workshop on participant engagement and health equity, focusing on the design of an inclusive cohort, building public trust, and identifying active participant engagement features for the national cohort. Precision techniques offer medical and public health practitioners the opportunity to personally tailor preventive and therapeutic regimens based on informatics applied to large volume genotypic and phenotypic data. The PMI's (All of Us Research Program's) medical and public health promise, its balanced attention to technical and ethical issues, and its nuanced advisory structure made it a natural choice for inclusion in the University of Michigan course "Issues in Public Health Genetics" (HMP 517), offered each fall by the University's School of Public Health. In 2015, the instructors included the PMI as the recurrent case study introduced at the beginning and referred to throughout the course, and as a class exercise allowing students to translate issues into policy. In 2016, an entire class session was devoted to precision medicine and precision public health. In this article, we examine the dialogues that transpired in these three course components, evaluate session impact on student ability to formulate PMI policy, and share our vision for next-generation courses dealing with precision health. Methodology: Class materials (class notes, oral exercise transcripts, class exercise written hand-ins) from the three course components were inspected and analyzed for issues and policy content. The purpose of the analysis was to assess the extent to which course components have enabled our students to formulate policy in the precision public health area. Analysis of student comments responding to questions posed during the initial case study comprised the initial or "pre-" categories. Analysis of student responses to the class exercise assignment, which included the same set of questions, formed the "post-" categories. Categories were validated by cross-comparison among the three authors, and inspected for frequency with which they appeared in student responses. Frequencies steered the selection of illustrative quotations, revealing the extent to which students were able to convert issue areas into actual policies. Lecture content and student comments in the precision health didactic session were inspected for degree to which they reinforced and extended the derived categories. Results: The case study inspection yielded four overarching categories: (1) assurance (access, equity, disparities); (2) participation (involvement, representativeness); (3) ethics (consent, privacy, benefit sharing); and (4) treatment of people (stigmatization, discrimination). Class exercise inspection and analysis yielded three additional categories: (5) financial; (6) educational; and (7) trust-building. The first three categories exceeded the others in terms of number of student mentions (8⁻14 vs. 4⁻6 mentions). Three other categories were considered and excluded because of infrequent mention. Students suggested several means of trust-building, including PMI personnel working with community leaders, stakeholder consultation, networking, and use of social media. Student representatives prioritized participant and research institution access to PMI information over commercial access. Multiple schemes were proposed for participant consent and return of results. Both pricing policy and Medicaid coverage were touched on. During the didactic session, students commented on the importance of provider training in precision health. Course evaluation highlighted the need for clarity on the organizations involved in the PMI, and leaving time for student-student interaction. Conclusions: While some student responses during the exercise were terse, an evolution was detectable over the three course components in student ability to suggest tangible policies and steps for implementation. Students also gained surety in presenting policy positions to a peer audience. Students came up with some very creative suggestions, such as use of an electronic platform to assure participant involvement in the disposition of their biological sample and personal health information, and alternate examples of ways to manage large volumes of data. An examination of socio-ethical issues and policies can strengthen student understanding of the directions the Precision Medicine Initiative is taking, and aid in training for the application of more varied precision medicine and public health techniques, such as tier 1 genetic testing and whole genome and exome sequencing. Future course development may reflect additional features of the ongoing All of Us Research Program, and further articulate precision public health approaches applying to populations as opposed to single individuals.

PMID: 30081448 [PubMed]

A novel homozygous mutation in PVRL4 causes ectodermal dysplasia-syndactyly syndrome 1.

Int J Dermatol. 2018 Feb;57(2):223-226

Authors: Florian R, Gruber R, Volc-Platzer B

Abstract
Ectodermal dysplasias (EDs) are a group of hereditary disorders defined by alterations in two or more ectodermal structures. One recently described rare entity is the autosomal recessive inherited ectodermal dysplasia-syndactyly syndrome 1 (EDSS1). Homozygous and compound heterozygous missense and nonsense mutations in the poliovirus receptor related-4 (PVRL4) gene, encoding cell adhesion molecule nectin-4, have been identified as causal for EDSS1. We here report a consanguineous family with a 2-year-old girl featuring EDSS1, including slowly progressive alopecia on the head, pili torti-like twisted hairs in trichoscopy, widely spaced, peg-shaped and conical teeth, proximal syndactyly with fusion of the 2nd to 4th toes, and generalized dry skin. There was no palmoplantar hyperkeratosis and sweating appeared normal to slightly enhanced, especially on the head. Using exome sequencing, we identified the novel homozygous nonsense mutation c.229C>T (p.Gln77Ter) in PVRL4.

PMID: 29265343 [PubMed - indexed for MEDLINE]

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Global genetic diversity of human apolipoproteins and effects on cardiovascular disease risk.

J Lipid Res. 2018 Aug 03;:

Authors: Zhou Y, Mägi R, Milani L, Lauschke VM

Abstract
Abnormal plasma apolipoprotein levels are consistently implicated in cardiovascular disease risk. Although 30% to 60% of their inter-individual variability is genetic, common genetic variants explain only 10% to 20% of these differences. Rare genetic variants may be major sources of the missing heritability, yet quantitative evaluations of their contribution to phenotypic variability are lacking. Here, we analyzed whole-genome and whole-exome sequencing data from 138,632 individuals across seven major human populations to present a systematic overview of genetic apolipoprotein variability. We provide population-specific frequencies of 38 clinically important apolipoprotein alleles and identified further 6,875 genetic variants, 33% of which were novel and 98.7% of which were rare with minor allele frequencies ≤1%. We predicted the functional impact of rare variants and found that their relative importance differed drastically between genes and among ethnicities. Importantly, we validated the clinical relevance of multiple variants with predicted effects by leveraging association data from the CARDIoGRAM and Global Lipids Genetics consortia. Overall, we provide a consolidated overview of population-specific apolipoprotein genetics as a valuable data resource for scientists and clinicians, estimate the importance of rare genetic variants for the missing heritability of apolipoprotein-associated disease traits and pinpoint multiple novel apolipoprotein variants with putative population-specific impacts on serum lipid levels.

PMID: 30076208 [PubMed - as supplied by publisher]

Contribution of noncoding pathogenic variants to RPGRIP1-mediated inherited retinal degeneration.

Genet Med. 2018 Aug 03;:

Authors: Jamshidi F, Place EM, Mehrotra S, Navarro-Gomez D, Maher M, Branham KE, Valkanas E, Cherry TJ, Lek M, MacArthur D, Pierce EA, Bujakowska KM

Abstract
PURPOSE: With the advent of gene therapies for inherited retinal degenerations (IRDs), genetic diagnostics will have an increasing role in clinical decision-making. Yet the genetic cause of disease cannot be identified using exon-based sequencing for a significant portion of patients. We hypothesized that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and evaluated patients with single coding pathogenic variants in RPGRIP1 to test this hypothesis.
METHODS: IRD families underwent targeted panel sequencing. Unsolved cases were explored by exome and genome sequencing looking for additional pathogenic variants. Candidate pathogenic variants were then validated by Sanger sequencing, quantitative polymerase chain reaction, and in vitro splicing assays in two cell lines analyzed through amplicon sequencing.
RESULTS: Among 1722 families, 3 had biallelic loss-of-function pathogenic variants in RPGRIP1 while 7 had a single disruptive coding pathogenic variants. Exome and genome sequencing revealed potential noncoding pathogenic variants in these 7 families. In 6, the noncoding pathogenic variants were shown to lead to loss of function in vitro.
CONCLUSION: Noncoding pathogenic variants were identified in 6 of 7 families with single coding pathogenic variants in RPGRIP1. The results suggest that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and RPGRIP1-mediated IRDs are more common than previously thought.

PMID: 30072743 [PubMed - as supplied by publisher]

Molecular genetics of Conn adenomas in the era of exome analysis.

Presse Med. 2018 Jul 30;:

Authors: El Zein RM, Boulkroun S, Fernandes-Rosa FL, Zennaro MC

Abstract
Aldosterone-producing adenomas (APA) are a major cause of primary aldosteronism (PA), the most common form of secondary hypertension. Exome analysis of APA has allowed the identification of recurrent somatic mutations in KCNJ5, CACNA1D, ATP1A1, and ATP2B3 in more than 50 % of sporadic cases. These gain of function mutations in ion channels and pumps lead to increased and autonomous aldosterone production. In addition, somatic CTNNB1 mutations have also been identified in APA. The CTNNB1 mutations were also identified in cortisol-producing adenomas and adrenal cancer, but their role in APA development and the mechanisms specifying the hormonal production or the malignant phenotype remain unknown. The role of the somatic mutations in the regulation of aldosterone production is well understood, while the impact of these mutations on cell proliferation remains to be established. Furthermore, the sequence of events leading to APA formation is currently the focus of many studies. There is evidence for a two-hit model where the somatic mutations are second hits occurring in a previously remodeled adrenal cortex. On the other hand, the APA-driver mutations were also identified in aldosterone-producing cell clusters (APCC) in normal adrenals, suggesting that these structures may represent precursors for APA development. As PA due to APA can be cured by surgical removal of the affected adrenal gland, the identification of the underlying genetic abnormalities by novel biomarkers could improve diagnostic and therapeutic approaches of the disease. In this context, recent data on steroid profiling in peripheral venous samples of APA patients and on new drugs capable of inhibiting mutated potassium channels provide promising preliminary data with potential for translation into clinical care.

PMID: 30072045 [PubMed - as supplied by publisher]

Polygenic Risk of Spasmodic Dysphonia is Associated With Vulnerable Sensorimotor Connectivity.

Cereb Cortex. 2018 Jan 01;28(1):158-166

Authors: Putzel GG, Battistella G, Rumbach AF, Ozelius LJ, Sabuncu MR, Simonyan K

Abstract
Spasmodic dysphonia (SD), or laryngeal dystonia, is an isolated task-specific dystonia of unknown causes and pathophysiology that selectively affects speech production. Using next-generation whole-exome sequencing in SD patients, we computed polygenic risk score from 1804 genetic markers based on a genome-wide association study in another form of similar task-specific focal dystonia, musician's dystonia. We further examined the associations between the polygenic risk score, resting-state functional connectivity abnormalities within the sensorimotor network, and SD clinical characteristics. We found that the polygenic risk of dystonia was significantly associated with decreased functional connectivity in the left premotor/primary sensorimotor and inferior parietal cortices in SD patients. Reduced connectivity of the inferior parietal cortex was correlated with the age of SD onset. The polygenic risk score contained a significant number of genetic variants lying near genes related to synaptic transmission and neural development. Our study identified a polygenic contribution to the overall genetic risk of dystonia in the cohort of SD patients. Associations between the polygenic risk and reduced functional connectivity of the sensorimotor and inferior parietal cortices likely represent an endophenotypic imaging marker of SD, while genes involved in synaptic transmission and neuron development may be linked to the molecular pathophysiology of this disorder.

PMID: 29117296 [PubMed - indexed for MEDLINE]

A family with floppy neonates with severe respiratory insufficiency: A lethal phenotype of RFT1-CDG due to a novel mutation.

Eur J Med Genet. 2018 Jul 30;:

Authors: Abiramalatha T, Arunachal G, Muthusamy K, Thomas N

Abstract
Congenital disorders of glycosylation (CDG) are a rapidly expanding group of inborn errors of metabolism with around 100 types described so far. Because of the limited number of reported cases in each type except PMM2-CDG, the complete clinical picture of other types is not known. RFT1-CDG is a rare type, with ten cases reported in the literature. Our patient presented as a floppy neonate with severe respiratory insufficiency and ventilator dependence in the newborn period. He had fetal growth restriction, facial dysmorphism, high arched palate, bilateral cryptorchidism, hypoplastic pons and cerebellum and probable hearing impairment. He succumbed to the illness on day 24 of life. There was a similar history of two previous sibling deaths in the early neonatal period due to respiratory insufficiency and history of multiple neonatal and infant deaths in the extended family. Transferrin iso-electric focusing was normal. Clinical exome sequencing revealed a novel homozygous missense mutation (c.1018 G > A) in RFT1 gene [NM_052859; c.1018G > A; p.G340S; ENST00000296292] and the parents were heterozygous for the same (ClinVar SVC000778540). The pathogenic variants so far reported are all missense variants affecting the luminal loops; whereas the variant in our case is in the trans-membrane helical domain. A strong family history of neonatal deaths and similar presentations in the previous 2 siblings suggests the homogenous phenotype of this mutation. Severe respiratory insuffiency and ventilator dependence shows the lethality of the disease phenotype and incompatibility with survival beyond the neonatal period.

PMID: 30071302 [PubMed - as supplied by publisher]

Heterozygous versus homozygous phenotype caused by the same MC4R mutation: novel mutation affecting a large consanguineous kindred.

BMC Med Genet. 2018 Aug 02;19(1):135

Authors: Drabkin M, Birk OS, Birk R

Abstract
BACKGROUND: The hypothalamic G-protein-coupled-receptor melanocortin-4 receptor (MC4R) is a key player in the central circuit regulating energy expenditure and appetite. Heterozygous loss-of-function MC4R mutations are the most common known genetic cause of monogenic human obesity, with more than 200 mutations described to date, affecting 2-3% of the population in various cohorts tested. Homozygous or compound heterozygous MC4R mutations are much less frequent, and only few families have been described in which heterozygotes and homozygotes of the same mutation are found.
METHODS: We performed exome sequencing in a consanguineous Bedouin family with morbid obesity to identify the genetic cause of the disease. Clinical examination and biochemical assays were done to delineate the phenotype.
RESULTS: We report the frequency of MC4R mutations in the large inbred Bedouin Israeli population. Furthermore, we describe consanguineous inbred Bedouin kindred with multiple individuals that are either homozygous or heterozygous carries of the same novel MC4R mutation (c.124G > T, p.E42*). All family members with the homozygous mutation exhibited morbid early-onset obesity, while heterozygote individuals had either a milder overweight phenotype or no discernable phenotype compared to wild type family members. While elder individuals homozygous or heterozygous for the MC4R mutation had abnormally high triglycerides, cholesterol, glucose and HbA1C levels, most did not.
CONCLUSIONS: MC4R mutation homozygotes exhibited morbid early-onset obesity, while heterozygotes had a significantly milder overweight phenotype. Whereas obesity due to MC4R mutations is evident as of early age - most notably in homozygotes, the metabolic consequences emerge only later in life.

PMID: 30068297 [PubMed - in process]

Ellis-van Creveld syndrome and profound deafness resulted by sequence variants in the EVC/EVC2 and TMC1 genes.

J Genet. 2017 Dec;96(6):1005-1014

Authors: Umair M, Seidel H, Ahmed I, Ullah A, Haack TB, Alhaddad B, Jan A, Rafique A, Strom TM, Ahmad F, Meitinger T, Ahmad W

Abstract
Ellis-van Creveld syndrome is an autosomal recessive skeletal dysplasia primarily characterized by the features such as disproportionate dwarfism, short ribs, short limbs, dysplastic nails, cardiovascular malformations, post-axial polydactyly (PAP) (bilateral) of hands and feet. EVC/EVC2 located in head-to-head arrangement on chromosome 4p16 are the causative genes for EvC syndrome. In the study, we present two families, A and B, with Pakistani and Republic of Kosovo origin, respectively. They showed features of EvC syndrome and were clinically and genetically characterized. In family A, the affected members showed an additional feature of profound deafness. The whole exome sequencing (WES) in this family revealed two homozygous variants in EVC2 (c.30dupC; p.Thr11Hisfs*45) and TMC1 (c.1696-1G>A) genes. In family B, WES revealed novel compound heterozygous variants (p.Ser307Pro, c.2894+3A>G) in the EVC gene. This study reports first case of variants in the genes causing EvC syndrome and profound deafness in the same family.

PMID: 29321360 [PubMed - indexed for MEDLINE]