@article {840, title = {Determinants of telomere length across human tissues.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, abstract = {

Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.

}, keywords = {Aging, Genetic Markers, Genetic Variation, Humans, Organ Specificity, Telomere, Telomere Homeostasis, Telomere Shortening}, issn = {1095-9203}, doi = {10.1126/science.aaz6876}, author = {Demanelis, Kathryn and Jasmine, Farzana and Chen, Lin S and Chernoff, Meytal and Tong, Lin and Delgado, Dayana and Zhang, Chenan and Shinkle, Justin and Sabarinathan, Mekala and Lin, Hannah and Ramirez, Eduardo and Oliva, Meritxell and Kim-Hellmuth, Sarah and Stranger, Barbara E and Lai, Tsung-Po and Aviv, Abraham and Ardlie, Kristin G and Aguet, Francois and Ahsan, Habibul and Doherty, Jennifer A and Kibriya, Muhammad G and Pierce, Brandon L} } @article {885, title = {Evaluation of the VISAGE Basic Tool for Appearance and Ancestry Prediction Using PowerSeq Chemistry on the MiSeq FGx System.}, journal = {Genes (Basel)}, volume = {11}, year = {2020}, month = {2020 06 26}, abstract = {

The study of DNA to predict externally visible characteristics (EVCs) and the biogeographical ancestry (BGA) from unknown samples is gaining relevance in forensic genetics. Technical developments in Massively Parallel Sequencing (MPS) enable the simultaneous analysis of hundreds of DNA markers, which improves successful Forensic DNA Phenotyping (FDP). The EU-funded VISAGE (VISible Attributes through GEnomics) Consortium has developed various targeted MPS-based lab tools to apply FDP in routine forensic analyses. Here, we present an evaluation of the VISAGE Basic tool for appearance and ancestry prediction based on PowerSeq chemistry (Promega) on a MiSeq FGx System (Illumina). The panel consists of 153 single nucleotide polymorphisms (SNPs) that provide information about EVCs (41 SNPs for eye, hair and skin color from HIrisPlex-S) and continental BGA (115 SNPs; three overlap with the EVCs SNP set). The assay was evaluated for sensitivity, repeatability and genotyping concordance, as well as its performance with casework-type samples. This targeted MPS assay provided complete genotypes at all 153 SNPs down to 125 pg of input DNA and 99.67\% correct genotypes at 50 pg. It was robust in terms of repeatability and concordance and provided useful results with casework-type samples. The results suggest that this MPS assay is a useful tool for basic appearance and ancestry prediction in forensic genetics for users interested in applying PowerSeq chemistry and MiSeq for this purpose.

}, keywords = {DNA Fingerprinting, Eye Color, Forensic Genetics, Genetic Markers, Genotype, Hair Color, High-Throughput Nucleotide Sequencing, Humans, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Skin Pigmentation, Software}, issn = {2073-4425}, doi = {10.3390/genes11060708}, author = {Palencia-Madrid, Leire and Xavier, Catarina and de la Puente, Maria and Hohoff, Carsten and Phillips, Christopher and Kayser, Manfred and Parson, Walther} } @article {863, title = {Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease.}, journal = {BMC Med Genomics}, volume = {13}, year = {2020}, month = {2020 08 26}, pages = {120}, abstract = {

BACKGROUND: Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of early AMD.

METHODS: To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants.

RESULTS: Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P~< 5 {\texttimes} 10), (ii) one previously suggested locus with experiment-wise significance (P~< 0.05/14) in our non-overlapping data and with genome-wide significance when combining the reported and our non-overlapping data (together 17,539 cases, 105,395 controls), and (iii) one further previously suggested locus with experiment-wise significance in our non-overlapping data. Of these 10 identified loci, 8 were novel and 2 known for early AMD. Most of the 10 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, C2, C3, CETP, TNFRSF10A, VEGFA, APOE), except two that have not yet been identified with statistical significance for any AMD. Among the 17 genes within these two loci, in-silico functional annotation suggested CD46 and TYR as the most likely responsible genes. Presence or absence of an early AMD effect distinguished the known pathways of advanced AMD genetics (complement/lipid pathways versus extracellular matrix metabolism).

CONCLUSIONS: Our GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD.

}, keywords = {Case-Control Studies, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Macular Degeneration, Polymorphism, Single Nucleotide}, issn = {1755-8794}, doi = {10.1186/s12920-020-00760-7}, author = {Winkler, Thomas W and Grassmann, Felix and Brandl, Caroline and Kiel, Christina and G{\"u}nther, Felix and Strunz, Tobias and Weidner, Lorraine and Zimmermann, Martina E and Korb, Christina A and Poplawski, Alicia and Schuster, Alexander K and M{\"u}ller-Nurasyid, Martina and Peters, Annette and Rauscher, Franziska G and Elze, Tobias and Horn, Katrin and Scholz, Markus and Ca{\~n}adas-Garre, Marisa and McKnight, Amy Jayne and Quinn, Nicola and Hogg, Ruth E and K{\"u}chenhoff, Helmut and Heid, Iris M and Stark, Klaus J and Weber, Bernhard H F} } @article {826, title = {Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families.}, journal = {BMC Med Genomics}, volume = {13}, year = {2020}, month = {2020 05 13}, pages = {68}, abstract = {

BACKGROUND: The causes for thousands of individually rare recessive diseases have been discovered since the adoption of next generation sequencing (NGS). Following the molecular diagnosis in older children in a family, parents could use this information to opt for fetal genotyping in subsequent pregnancies, which could inform decisions about elective termination of pregnancy. The use of NGS diagnostic sequencing in families has not been demonstrated to yield benefit in subsequent pregnancies to reduce recurrence. Here we evaluated whether genetic diagnosis in older children in families supports reduction in recurrence of recessive neurogenetic disease.

METHODS: Retrospective study involving families with a child with a recessive pediatric brain disease (rPBD) that underwent NGS-based molecular diagnosis. Prenatal molecular testing was offered to couples in which a molecular diagnosis was made, to help couples seeking to prevent recurrence. With this information, families made decisions about elective termination. Pregnancies that were carried to term were assessed for the health of child and mother, and compared with historic recurrence risk of recessive disease.

RESULTS: Between 2010 and 2016, 1172 families presented with a child a likely~rPBD, 526 families received a molecular diagnosis, 91 families returned to the clinic with 101 subsequent pregnancies, and 84 opted for fetal genotyping. Sixty tested negative for recurrence for the biallelic mutation~in the fetus, and all, except for one spontaneous abortion, carried to term, and were unaffected at follow-up. Of 24 that genotyped positive~for~the biallelic mutation, 16 were electively terminated, and 8 were carried to term and showed features of disease similar to that of the older~affected sibling(s). Among the 101 pregnancies, disease recurrence in living offspring deviated from the expected 25\% to the observed 12\% ([95\% CI 0{\textperiodcentered}04 to 0{\textperiodcentered}20], p = 0{\textperiodcentered}011).

CONCLUSIONS: Molecular diagnosis in an older child, coupled with prenatal fetal genotyping in subsequent pregnancies and genetic counselling, allows families to make informed decisions to reduce recessive neurogenetic disease recurrence.

}, keywords = {Child, Preschool, Female, Genes, Recessive, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genotype, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Male, Mutation, Nervous System Diseases, Pedigree, Pregnancy, Prenatal Diagnosis, Recurrence, Retrospective Studies}, issn = {1755-8794}, doi = {10.1186/s12920-020-0714-1}, author = {Issa, Mahmoud Y and Chechlacz, Zinayida and Stanley, Valentina and George, Renee D and McEvoy-Venneri, Jennifer and Belandres, Denice and Elbendary, Hasnaa M and Gaber, Khaled R and Nabil, Ahmed and Abdel-Hamid, Mohamed S and Zaki, MAH S and Gleeson, Joseph G} } @article {852, title = {Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression.}, journal = {Genes (Basel)}, volume = {11}, year = {2020}, month = {2020 07 25}, abstract = {

Approximately 30\% of individuals with autism spectrum disorder (ASD) experience developmental regression, the etiology of which remains largely unknown. We performed a complete literature search and identified 47 genes that had been implicated in such cases. We sequenced these genes in a preselected cohort of 134 individuals with regressive autism. In total, 16 variants in 12 genes with evidence supportive of pathogenicity were identified. They were classified as variants of uncertain significance based on ACMG standards and guidelines. Among these were recurring variants in and , variants in genes that were linked to syndromic forms of ASD (, , , , , and ), and variants in the form of oligogenic heterozygosity (, , and ).

}, keywords = {Autism Spectrum Disorder, Child, Child, Preschool, Cohort Studies, Disease Progression, Female, Gene Expression Regulation, Genetic Markers, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Mutation}, issn = {2073-4425}, doi = {10.3390/genes11080853}, author = {Yin, Jiani and Chun, Chun-An and Zavadenko, Nikolay N and Pechatnikova, Natalia L and Naumova, Oxana Yu and Doddapaneni, Harsha V and Hu, Jianhong and Muzny, Donna M and Schaaf, Christian P and Grigorenko, Elena L} } @article {538, title = {Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies.}, journal = {Hum Mutat}, volume = {39}, year = {2018}, month = {2018 01}, pages = {152-166}, abstract = {

Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis-van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes. The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.

}, keywords = {Ciliopathies, Cytoplasmic Dyneins, Genetic Association Studies, Genetic Markers, Genetic Variation, Genotype, Humans, Mutation, Phenotype, Proteins, Radiography, Skeleton, Whole Exome Sequencing}, issn = {1098-1004}, doi = {10.1002/humu.23362}, author = {Zhang, Wenjuan and Taylor, S Paige and Ennis, Hayley A and Forlenza, Kimberly N and Duran, Ivan and Li, Bing and Sanchez, Jorge A Ortiz and Nevarez, Lisette and Nickerson, Deborah A and Bamshad, Michael and Lachman, Ralph S and Krakow, Deborah and Cohn, Daniel H} } @article {500, title = {Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Sep}, pages = {753-768}, abstract = {

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant~located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.

}, keywords = {Adolescent, Adult, Carrier Proteins, Channelopathies, Child, Child, Preschool, Developmental Disabilities, Female, Genetic Markers, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Phenotype, Sodium Channels, Young Adult}, issn = {1432-1203}, doi = {10.1007/s00439-018-1929-5}, author = {Bramswig, Nuria C and Bertoli-Avella, Aida M and Albrecht, Beate and Al Aqeel, Aida I and Alhashem, Amal and Al-Sannaa, Nouriya and Bah, Maissa and Br{\"o}hl, Katharina and Depienne, Christel and Dorison, Nathalie and Doummar, Diane and Ehmke, Nadja and Elbendary, Hasnaa M and Gorokhova, Svetlana and H{\'e}ron, Delphine and Horn, Denise and James, Kiely and Keren, Boris and Kuechler, Alma and Ismail, Samira and Issa, Mahmoud Y and Marey, Isabelle and Mayer, Mich{\`e}le and McEvoy-Venneri, Jennifer and Megarbane, Andre and Mignot, Cyril and Mohamed, Sarar and Nava, Caroline and Philip, Nicole and Ravix, Cecile and Rolfs, Arndt and Sadek, Abdelrahim Abdrabou and Segebrecht, Lara and Stanley, Valentina and Trautman, Camille and Valence, Stephanie and Villard, Laurent and Wieland, Thomas and Engels, Hartmut and Strom, Tim M and Zaki, Maha S and Gleeson, Joseph G and L{\"u}decke, Hermann-Josef and Bauer, Peter and Wieczorek, Dagmar} } @article {523, title = {Identification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR, and WNT10A in four Turkish families with tooth agenesis.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Sep}, pages = {689-703}, abstract = {

Tooth agenesis (TA), the failure of development of one or more permanent teeth, is a common craniofacial abnormality observed in different world populations. The genetic etiology of TA is heterogeneous; more than a dozen genes have been associated with isolated or nonsyndromic TA, and more than 80 genes with syndromic forms. In this study, we applied whole exome sequencing (WES) to identify candidate genes contributing to TA in four Turkish families. Likely pathogenic variants with a low allele frequency in the general population were identified in four disease-associated genes, including two distinct variants in TSPEAR, associated with syndromic and isolated TA in one family each; a variant in LAMB3 associated with syndromic TA in one family; and a variant in BCOR plus a disease-associated WNT10A variant in one family with syndromic TA. With the notable exception of WNT10A (Tooth agenesis, selective, 4, MIM $\#$150400), the genotype-phenotype relationships described in the present cohort represent an expansion of the clinical spectrum associated with these genes: TSPEAR (Deafness, autosomal recessive 98, MIM $\#$614861), LAMB3 (Amelogenesis imperfecta, type IA, MIM $\#$104530; Epidermolysis bullosa, junctional, MIMs $\#$226700 and $\#$226650), and BCOR (Microphthalmia, syndromic 2, MIM $\#$300166). We provide evidence supporting the candidacy of these genes with TA, and propose TSPEAR as a novel nonsyndromic TA gene. Our data also suggest potential multilocus genomic variation, or mutational burden, in a single family, involving the BCOR and WNT10A loci, underscoring the complexity of the genotype-phenotype relationship in the common complex trait of TA.

}, keywords = {Anodontia, Cell Adhesion Molecules, Child, Child, Preschool, Female, Genetic Markers, Humans, Male, Mutation, Pedigree, Phenotype, Proteins, Proto-Oncogene Proteins, Repressor Proteins, Turkey, Wnt Proteins}, issn = {1432-1203}, doi = {10.1007/s00439-018-1907-y}, author = {Du, Renqian and Dinckan, Nuriye and Song, Xiaofei and Coban-Akdemir, Zeynep and Jhangiani, Shalini N and Guven, Yeliz and Aktoren, Oya and Kayserili, H{\"u}lya and Petty, Lauren E and Muzny, Donna M and Below, Jennifer E and Boerwinkle, Eric and Wu, Nan and Gibbs, Richard A and Posey, Jennifer E and Lupski, James R and Letra, Ariadne and Uyguner, Z Oya} } @article {498, title = {Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Sep}, pages = {735-752}, abstract = {

Identification of Mendelian genes for neurodevelopmental disorders using exome sequencing to study autosomal recessive (AR) consanguineous pedigrees has been highly successful. To identify causal variants for syndromic and non-syndromic intellectual disability (ID), exome sequencing was performed using DNA samples from 22 consanguineous Pakistani families with ARID, of which 21 have additional phenotypes including microcephaly. To aid in variant identification, homozygosity mapping and linkage analysis were performed. DNA samples from affected family member(s) from every pedigree underwent exome sequencing. Identified rare damaging exome variants were tested for co-segregation with ID using Sanger sequencing. For seven ARID families, variants were identified in genes not previously associated with ID, including: EI24, FXR1 and TET3 for which knockout mouse models have brain defects; and CACNG7 and TRAPPC10 where cell studies suggest roles in important neural pathways. For two families, the novel ARID genes CARNMT1 and GARNL3 lie within previously reported ID microdeletion regions. We also observed homozygous variants in two ID candidate genes, GRAMD1B and TBRG1, for which each has been previously reported in a single family. An additional 14 families have homozygous variants in established ID genes, of which 11 variants are novel. All ARID genes have increased expression in specific structures of the developing and adult human brain and 91\% of the genes are differentially expressed in utero or during early childhood. The identification of novel ARID candidate genes and variants adds to the knowledge base that is required to further understand human brain function and development.

}, keywords = {Adult, Consanguinity, Family, Female, Genes, Recessive, Genetic Markers, Humans, Intellectual Disability, Male, Middle Aged, Mutation, Neurodevelopmental Disorders, Pedigree}, issn = {1432-1203}, doi = {10.1007/s00439-018-1928-6}, author = {Santos-Cortez, Regie Lyn P and Khan, Valeed and Khan, Falak Sher and Mughal, Zaib-Un-Nisa and Chakchouk, Imen and Lee, Kwanghyuk and Rasheed, Memoona and Hamza, Rifat and Acharya, Anushree and Ullah, Ehsan and Saqib, Muhammad Arif Nadeem and Abbe, Izoduwa and Ali, Ghazanfar and Hassan, Muhammad Jawad and Khan, Saadullah and Azeem, Zahid and Ullah, Irfan and Bamshad, Michael J and Nickerson, Deborah A and Schrauwen, Isabelle and Ahmad, Wasim and Ansar, Muhammad and Leal, Suzanne M} } @article {441, title = {Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and~nephrocalcinosis.}, journal = {Kidney Int}, volume = {93}, year = {2018}, month = {2018 01}, pages = {204-213}, abstract = {

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4\% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8\% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.

}, keywords = {Adolescent, Age of Onset, Child, Child, Preschool, Disease Progression, Female, Genetic Association Studies, Genetic Markers, Genetic Predisposition to Disease, Heredity, Humans, Infant, Male, Mutation, Nephrocalcinosis, Nephrolithiasis, Pedigree, Phenotype, Predictive Value of Tests, Prognosis, Risk Factors, Tomography, X-Ray Computed, Ultrasonography, Whole Exome Sequencing, Young Adult}, issn = {1523-1755}, doi = {10.1016/j.kint.2017.06.025}, author = {Daga, Ankana and Majmundar, Amar J and Braun, Daniela A and Gee, Heon Yung and Lawson, Jennifer A and Shril, Shirlee and Jobst-Schwan, Tilman and Vivante, Asaf and Schapiro, David and Tan, Weizhen and Warejko, Jillian K and Widmeier, Eugen and Nelson, Caleb P and Fathy, Hanan M and Gucev, Zoran and Soliman, Neveen A and Hashmi, Seema and Halbritter, Jan and Halty, Margarita and Kari, Jameela A and El-Desoky, Sherif and Ferguson, Michael A and Somers, Michael J G and Traum, Avram Z and Stein, Deborah R and Daouk, Ghaleb H and Rodig, Nancy M and Katz, Avi and Hanna, Christian and Schwaderer, Andrew L and Sayer, John A and Wassner, Ari J and Mane, Shrikant and Lifton, Richard P and Milosevic, Danko and Tasic, Velibor and Baum, Michelle A and Hildebrandt, Friedhelm} } @article {365, title = {Diagnosis of Chronic Intestinal Pseudo-obstruction and Megacystis by Sequencing the ACTG2 Gene.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {65}, year = {2017}, month = {2017 10}, pages = {384-387}, abstract = {

OBJECTIVES: The diagnosis of chronic intestinal pseudo-obstruction has depended on clinical features, manometry, and imaging. This report aimed to determine the efficacy of sequencing the actin γ-2 (ACTG2) gene for diagnosis. In addition, the goal was to determine how often a mutation would be found in our randomly collected cohort of probands and those probands published previously.

METHODS: Whole exome sequencing was performed in 4 probands with chronic intestinal pseudo-obstruction. Subsequently, only the ACTG2 gene was sequenced in another 24 probands (total 28). We analyzed published data of 83 probands and our 28 (total 111) and determined how many had pathogenic variants and the precise genotype.

RESULTS: Whole exome and Sanger sequencing revealed a pathogenic variant in the ACTG2 gene in 4 out of 28 of our probands and in 45 out of 83 published probands (49/111 [44.1\%]). Moreover, a mutational hotspot in the ACTG2 gene was recognized. Genetic heterogeneity is evident.

CONCLUSIONS: Pooled gene sequencing results from 1 individual in each of 111 families enabled a precise diagnosis of an ACTG2 mutation in 49 (44\%). The benefit to patients and families of early confirmation of a motility disorder not only helps avoid unnecessary intervention, but also enables institution of appropriate treatments and avoidance of secondary disorders such as malnutrition and poor growth. Knowledge of a pathogenic variant in a parent, with a 50\% risk of recurrence, provides an opportunity for genetic counseling.

}, keywords = {Actins, Adult, Child, Child, Preschool, Chronic Disease, Duodenum, Female, Fetal Diseases, Genetic Markers, Genetic Testing, Humans, Infant, Infant, Newborn, Intestinal Pseudo-Obstruction, Male, Mutation, Sequence Analysis, DNA, Urinary Bladder, Whole Exome Sequencing}, issn = {1536-4801}, doi = {10.1097/MPG.0000000000001608}, author = {Milunsky, Aubrey and Baldwin, Clinton and Zhang, Xiaoying and Primack, Daniel and Curnow, Adrian and Milunsky, Jeff} } @article {40, title = {Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery.}, journal = {Nat Genet}, volume = {48}, year = {2016}, month = {2016 09}, pages = {1071-6}, abstract = {

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia, has resulted in an elevated burden of recessive disease. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized {\textquoteright}genetic purging{\textquoteright}. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics.

}, keywords = {Asian Continental Ancestry Group, Cohort Studies, Consanguinity, Disease, European Continental Ancestry Group, Exome, Genes, Recessive, Genetic Markers, Genetic Variation, Genetics, Population, Genome, Human, Genome-Wide Association Study, Homozygote, Human Migration, Humans, Middle East}, issn = {1546-1718}, doi = {10.1038/ng.3592}, author = {Scott, Eric M and Halees, Anason and Itan, Yuval and Spencer, Emily G and He, Yupeng and Azab, Mostafa Abdellateef and Gabriel, Stacey B and Belkadi, Aziz and Boisson, Bertrand and Abel, Laurent and Clark, Andrew G and Alkuraya, Fowzan S and Casanova, Jean-Laurent and Gleeson, Joseph G} } @article {148, title = {An siRNA-based functional genomics screen for the~identification of regulators of ciliogenesis and ciliopathy~genes.}, journal = {Nat Cell Biol}, volume = {17}, year = {2015}, month = {2015 Aug}, pages = {1074-1087}, abstract = {

Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1, also known as CEP90, and C21orf2, also known as LRRC76, as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.

}, keywords = {Abnormalities, Multiple, Animals, Caenorhabditis elegans, Cerebellar Diseases, Cerebellum, Cilia, Ciliary Motility Disorders, Databases, Genetic, Ellis-Van Creveld Syndrome, Eye Abnormalities, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genome-Wide Association Study, Genomics, HEK293 Cells, High-Throughput Nucleotide Sequencing, Humans, Kidney Diseases, Cystic, Membrane Proteins, Mice, Inbred C57BL, Mice, Knockout, Mutation, Phenotype, Photoreceptor Cells, Pregnancy Proteins, Proteins, Reproducibility of Results, Retina, RNA Interference, Suppressor Factors, Immunologic, Transfection, Zebrafish}, issn = {1476-4679}, doi = {10.1038/ncb3201}, author = {Wheway, Gabrielle and Schmidts, Miriam and Mans, Dorus A and Szymanska, Katarzyna and Nguyen, Thanh-Minh T and Racher, Hilary and Phelps, Ian G and Toedt, Grischa and Kennedy, Julie and Wunderlich, Kirsten A and Sorusch, Nasrin and Abdelhamed, Zakia A and Natarajan, Subaashini and Herridge, Warren and van Reeuwijk, Jeroen and Horn, Nicola and Boldt, Karsten and Parry, David A and Letteboer, Stef J F and Roosing, Susanne and Adams, Matthew and Bell, Sandra M and Bond, Jacquelyn and Higgins, Julie and Morrison, Ewan E and Tomlinson, Darren C and Slaats, Gisela G and van Dam, Teunis J P and Huang, Lijia and Kessler, Kristin and Giessl, Andreas and Logan, Clare V and Boyle, Evan A and Shendure, Jay and Anazi, Shamsa and Aldahmesh, Mohammed and Al Hazzaa, Selwa and Hegele, Robert A and Ober, Carole and Frosk, Patrick and Mhanni, Aizeddin A and Chodirker, Bernard N and Chudley, Albert E and Lamont, Ryan and Bernier, Francois P and Beaulieu, Chandree L and Gordon, Paul and Pon, Richard T and Donahue, Clem and Barkovich, A James and Wolf, Louis and Toomes, Carmel and Thiel, Christian T and Boycott, Kym M and McKibbin, Martin and Inglehearn, Chris F and Stewart, Fiona and Omran, Heymut and Huynen, Martijn A and Sergouniotis, Panagiotis I and Alkuraya, Fowzan S and Parboosingh, Jillian S and Innes, A Micheil and Willoughby, Colin E and Giles, Rachel H and Webster, Andrew R and Ueffing, Marius and Blacque, Oliver and Gleeson, Joseph G and Wolfrum, Uwe and Beales, Philip L and Gibson, Toby and Doherty, Dan and Mitchison, Hannah M and Roepman, Ronald and Johnson, Colin A} } @article {263, title = {Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype.}, journal = {Am J Respir Crit Care Med}, volume = {189}, year = {2014}, month = {2014 Mar 15}, pages = {707-17}, abstract = {

RATIONALE: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic cause is not defined for all patients with PCD.

OBJECTIVES: To identify disease-causing mutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in patients with PCD.

METHODS: Whole-exome sequencing was performed using NimbleGen capture and Illumina HiSeq sequencing. Sanger-based sequencing was used for mutation scanning, validation, and segregation analysis.

MEASUREMENTS AND MAIN RESULTS: We performed exome sequencing on an affected sib-pair with normal ultrastructure in more than 85\% of cilia. A homozygous splice-site mutation was detected in RSPH1 in both siblings; parents were carriers. Screening RSPH1 in 413 unrelated probands, including 325 with PCD and 88 with idiopathic bronchiectasis, revealed biallelic loss-of-function mutations in nine additional probands. Five affected siblings of probands in RSPH1 families harbored the familial mutations. The 16 individuals with RSPH1 mutations had some features of PCD; however, nasal nitric oxide levels were higher than in patients with PCD with other gene mutations (98.3 vs. 20.7 nl/min; P < 0.0003). Additionally, individuals with RSPH1 mutations had a lower prevalence (8 of 16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEV1), compared with 75 age- and sex-matched PCD cases (73.0 vs. 61.8, FEV1 \% predicted; P = 0.043). Cilia from individuals with RSPH1 mutations had normal beat frequency (6.1 {\textpm} Hz at 25{\textdegree}C), but an abnormal, circular beat pattern.

CONCLUSIONS: The milder clinical disease and higher nasal nitric oxide in individuals with biallelic mutations in RSPH1 provides evidence of a unique genotype-phenotype relationship in PCD, and suggests that mutations in RSPH1 may be associated with residual ciliary function.

}, keywords = {Adolescent, Adult, Child, Cilia, DNA Mutational Analysis, DNA-Binding Proteins, Exome, Female, Genetic Association Studies, Genetic Markers, Genetic Testing, Homozygote, Humans, Kartagener Syndrome, Linear Models, Male, Middle Aged, Mutation, Nasal Mucosa, Sequence Analysis, DNA, Young Adult}, issn = {1535-4970}, doi = {10.1164/rccm.201311-2047OC}, author = {Knowles, Michael R and Ostrowski, Lawrence E and Leigh, Margaret W and Sears, Patrick R and Davis, Stephanie D and Wolf, Whitney E and Hazucha, Milan J and Carson, Johnny L and Olivier, Kenneth N and Sagel, Scott D and Rosenfeld, Margaret and Ferkol, Thomas W and Dell, Sharon D and Milla, Carlos E and Randell, Scott H and Yin, Weining and Sannuti, Aruna and Metjian, Hilda M and Noone, Peadar G and Noone, Peter J and Olson, Christina A and Patrone, Michael V and Dang, Hong and Lee, Hye-Seung and Hurd, Toby W and Gee, Heon Yung and Otto, Edgar A and Halbritter, Jan and Kohl, Stefan and Kircher, Martin and Krischer, Jeffrey and Bamshad, Michael J and Nickerson, Deborah A and Hildebrandt, Friedhelm and Shendure, Jay and Zariwala, Maimoona A} }