@article {941, title = {MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia.}, journal = {Ann Neurol}, volume = {89}, year = {2021}, month = {2021 04}, pages = {828-833}, abstract = {

The Mediator multiprotein complex functions as a regulator of RNA polymerase II-catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021;89:828-833.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Cataract, Cerebellum, Child, Child, Preschool, Developmental Disabilities, Dystonia, Epilepsy, Genetic Variation, Humans, Infant, Mediator Complex, Nervous System Malformations, Phenotype, Whole Exome Sequencing}, issn = {1531-8249}, doi = {10.1002/ana.26019}, author = {Meng, Linyan and Isohanni, Pirjo and Shao, Yunru and GrAHm, Brett H and Hickey, Scott E and Brooks, Stephanie and Suomalainen, Anu and Joset, Pascal and Steindl, Katharina and Rauch, Anita and Hackenberg, Annette and High, Frances A and Armstrong-Javors, Amy and Mencacci, Niccol{\`o} E and Gonz{\`a}lez-Latapi, Paulina and Kamel, Walaa A and Al-Hashel, Jasem Y and Bustos, Bernab{\'e} I and Hernandez, Alejandro V and Krainc, Dimitri and Lubbe, Steven J and Van Esch, Hilde and De Luca, Chiara and Ballon, Katleen and Ravelli, Claudia and Burglen, Lydie and Qebibo, Leila and Calame, Daniel G and Mitani, Tadahiro and Marafi, Dana and Pehlivan, Davut and Saadi, Nebal W and Sahin, Yavuz and Maroofian, Reza and Efthymiou, Stephanie and Houlden, Henry and Maqbool, Shazia and Rahman, Fatima and Gu, Shen and Posey, Jennifer E and Lupski, James R and Hunter, Jill V and Wangler, Michael F and Carroll, Christopher J and Yang, Yaping} } @article {27, title = {Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.}, journal = {J Allergy Clin Immunol}, volume = {139}, year = {2017}, month = {2017 Jan}, pages = {232-245}, abstract = {

BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions.

OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.

METHODS: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping.

RESULTS: A likely molecular diagnosis was achieved in 110 (40\%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30~Kb that would not have been detected with conventional diagnostic CNV arrays.

CONCLUSION: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

}, keywords = {Adolescent, Adult, Aged, Child, Child, Preschool, DNA Copy Number Variations, Female, Genomics, High-Throughput Nucleotide Sequencing, Humans, Immunologic Deficiency Syndromes, Infant, Male, Middle Aged, Young Adult}, issn = {1097-6825}, doi = {10.1016/j.jaci.2016.05.042}, author = {Stray-Pedersen, Asbj{\o}rg and Sorte, Hanne S{\o}rmo and Samarakoon, Pubudu and Gambin, Tomasz and Chinn, Ivan K and Coban Akdemir, Zeynep H and Erichsen, Hans Christian and Forbes, Lisa R and Gu, Shen and Yuan, Bo and Jhangiani, Shalini N and Muzny, Donna M and R{\o}dningen, Olaug Kristin and Sheng, Ying and Nicholas, Sarah K and Noroski, Lenora M and Seeborg, Filiz O and Davis, Carla M and Canter, Debra L and Mace, Emily M and Vece, Timothy J and Allen, Carl E and Abhyankar, Harshal A and Boone, Philip M and Beck, Christine R and Wiszniewski, Wojciech and Fevang, B{\o}rre and Aukrust, P{\r a}l and Tj{\o}nnfjord, Geir E and Gedde-Dahl, Tobias and Hjorth-Hansen, Henrik and Dybedal, Ingunn and Nord{\o}y, Ingvild and J{\o}rgensen, Silje F and Abrahamsen, Tore G and {\O}verland, Torstein and Bechensteen, Anne Grete and Skogen, Vegard and Osnes, Liv T N and Kulseth, Mari Ann and Prescott, Trine E and Rustad, Cecilie F and Heimdal, Ketil R and Belmont, John W and Rider, Nicholas L and Chinen, Javier and Cao, Tram N and Smith, Eric A and Caldirola, Maria Soledad and Bezrodnik, Liliana and Lugo Reyes, Saul Oswaldo and Espinosa Rosales, Francisco J and Guerrero-Cursaru, Nina Denisse and Pedroza, Luis Alberto and Poli, Cecilia M and Franco, Jose L and Trujillo Vargas, Claudia M and Aldave Becerra, Juan Carlos and Wright, Nicola and Issekutz, Thomas B and Issekutz, Andrew C and Abbott, Jordan and Caldwell, Jason W and Bayer, Diana K and Chan, Alice Y and Aiuti, Alessandro and Cancrini, Caterina and Holmberg, Eva and West, Christina and Burstedt, Magnus and Karaca, Ender and Yesil, G{\"o}zde and Artac, Hasibe and Bayram, Yavuz and Atik, Mehmed Musa and Eldomery, Mohammad K and Ehlayel, Mohammad S and Jolles, Stephen and Flat{\o}, Berit and Bertuch, Alison A and Hanson, I Celine and Zhang, Victor W and Wong, Lee-Jun and Hu, Jianhong and Walkiewicz, Magdalena and Yang, Yaping and Eng, Christine M and Boerwinkle, Eric and Gibbs, Richard A and Shearer, William T and Lyle, Robert and Orange, Jordan S and Lupski, James R} } @article {119, title = {Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation.}, journal = {Hum Mutat}, volume = {37}, year = {2016}, month = {2016 Feb}, pages = {160-4}, abstract = {

Germline copy-number variants (CNVs) involving quadruplications are rare and the mechanisms generating them are largely unknown. Previously, we reported a 20-week gestation fetus with split-hand malformation; clinical microarray detected two maternally inherited triplications separated by a copy-number neutral region at 17p13.3, involving BHLHA9 and part of YWHAE. Here, we describe an 18-month-old male sibling of the previously described fetus with split-hand malformation. Custom high-density microarray and digital droplet PCR revealed the copy-number gains were actually quadruplications in the mother, the fetus, and her later born son. This quadruplication-normal-quadruplication pattern was shown to be expanded from the triplication-normal-triplication CNV at the same loci in the maternal grandmother. We mapped two breakpoint junctions and demonstrated that both are mediated by Alu repetitive elements and identical in these four individuals. We propose a three-step process combining Alu-mediated replicative-repair-based mechanism(s) and intergenerational, intrachromosomal nonallelic homologous recombination to generate the quadruplications in this family.

}, keywords = {14-3-3 Proteins, Adult, Aged, Alu Elements, Base Sequence, Basic Helix-Loop-Helix Transcription Factors, Chromosome Duplication, Chromosomes, Human, Pair 17, DNA Copy Number Variations, Female, Genetic Loci, Genome, Human, Hand Deformities, Congenital, Humans, Infant, Male, Molecular Sequence Data, Pedigree, Sequence Alignment, Sequence Analysis, DNA}, issn = {1098-1004}, doi = {10.1002/humu.22929}, author = {Gu, Shen and Posey, Jennifer E and Yuan, Bo and Carvalho, Claudia M B and Luk, H M and Erikson, Kelly and Lo, Ivan F M and Leung, Gordon K C and Pickering, Curtis R and Chung, Brian H Y and Lupski, James R} } @article {10, title = {MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death.}, journal = {Genome Med}, volume = {8}, year = {2016}, month = {2016 Nov 01}, pages = {106}, abstract = {

BACKGROUND: Mitochondrial presequence proteases perform fundamental functions as they process about 70~\% of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease.

METHODS: Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human.

RESULTS: Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients{\textquoteright} missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria.

CONCLUSIONS: Our findings reveal for the first time the role of the mitochondrial intermediate peptidase in human disease. Loss of MIP function results in a syndrome which consists of LVNC, DD, seizures, hypotonia, and cataracts. Our approach highlights the power of data exchange and the importance of an interrelationship between clinical and research efforts for disease gene discovery.

}, keywords = {Adult, Amino Acid Sequence, Female, Genes, Recessive, Heart Defects, Congenital, Humans, Infant, Infant, Newborn, Male, Metalloendopeptidases, Muscle Hypotonia, Pedigree, Phenotype, Sequence Homology, Amino Acid, Sudden Infant Death, Syndrome}, issn = {1756-994X}, doi = {10.1186/s13073-016-0360-6}, author = {Eldomery, Mohammad K and Akdemir, Zeynep C and V{\"o}gtle, F-Nora and Charng, Wu-Lin and Mulica, Patrycja and Rosenfeld, Jill A and Gambin, Tomasz and Gu, Shen and Burrage, Lindsay C and Al Shamsi, Aisha and Penney, Samantha and Jhangiani, Shalini N and Zimmerman, Holly H and Muzny, Donna M and Wang, Xia and Tang, Jia and Medikonda, Ravi and Ramachandran, Prasanna V and Wong, Lee-Jun and Boerwinkle, Eric and Gibbs, Richard A and Eng, Christine M and Lalani, Seema R and Hertecant, Jozef and Rodenburg, Richard J and Abdul-Rahman, Omar A and Yang, Yaping and Xia, Fan and Wang, Meng C and Lupski, James R and Meisinger, Chris and Sutton, V Reid} } @article {41, title = {Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith-Magenis syndrome with evident peripheral neuropathy.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 Oct}, pages = {1161-74}, abstract = {

Hereditary neuropathy with liability to pressure palsies (HNPP) and Smith-Magenis syndrome (SMS) are genomic disorders associated with deletion copy number variants involving chromosome 17p12 and 17p11.2, respectively. Nonallelic homologous recombination (NAHR)-mediated recurrent deletions are responsible for the majority of HNPP and SMS cases; the rearrangement products encompass the key dosage-sensitive genes PMP22 and RAI1, respectively, and result in haploinsufficiency for these genes. Less frequently, nonrecurrent genomic rearrangements occur at this locus. Contiguous gene duplications encompassing both PMP22 and RAI1, i.e., PMP22-RAI1 duplications, have been investigated, and replication-based mechanisms rather than NAHR have been proposed for these rearrangements. In the current study, we report molecular and clinical characterizations of six subjects with the reciprocal phenomenon of deletions spanning both genes, i.e., PMP22-RAI1 deletions. Molecular studies utilizing high-resolution array comparative genomic hybridization and breakpoint junction sequencing identified mutational signatures that were suggestive of replication-based mechanisms. Systematic clinical studies revealed features consistent with SMS, including features of intellectual disability, speech and gross motor delays, behavioral problems and ocular abnormalities. Five out of six subjects presented clinical signs and/or objective electrophysiologic studies of peripheral neuropathy. Clinical profiling may improve the clinical management of this unique group of subjects, as the peripheral neuropathy can be more severe or of earlier onset as compared to SMS patients having the common recurrent deletion. Moreover, the current study, in combination with the previous report of PMP22-RAI1 duplications, contributes to the understanding of rare complex phenotypes involving multiple dosage-sensitive genes from a genetic mechanistic standpoint.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Chromosomes, Human, Pair 17, DNA Copy Number Variations, DNA Replication, Female, Gene Deletion, Haploinsufficiency, Homologous Recombination, Humans, Intellectual Disability, Male, Mutation, Myelin Proteins, Smith-Magenis Syndrome, Trans-Activators, Transcription Factors}, issn = {1432-1203}, doi = {10.1007/s00439-016-1703-5}, author = {Yuan, Bo and Neira, Juanita and Gu, Shen and Harel, Tamar and Liu, Pengfei and Brice{\~n}o, Ignacio and Elsea, Sarah H and G{\'o}mez, Alberto and Potocki, Lorraine and Lupski, James R} } @article {21, title = {Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Oct 06}, pages = {831-845}, abstract = {

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of bor, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of bor resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

}, keywords = {Adenosine Triphosphatases, Adult, Alleles, Animals, ATPases Associated with Diverse Cellular Activities, Axons, Cardiomyopathies, Child, Child, Preschool, Developmental Disabilities, DNA Copy Number Variations, Drosophila melanogaster, Female, Fibroblasts, Homozygote, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Mitochondria, Mitochondrial Proteins, Muscle Hypotonia, Muscles, Mutation, Nervous System Diseases, Neurons, Optic Atrophy, Phenotype, Polymorphism, Single Nucleotide, Syndrome, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.08.007}, author = {Harel, Tamar and Yoon, Wan Hee and Garone, Caterina and Gu, Shen and Coban-Akdemir, Zeynep and Eldomery, Mohammad K and Posey, Jennifer E and Jhangiani, Shalini N and Rosenfeld, Jill A and Cho, Megan T and Fox, Stephanie and Withers, Marjorie and Brooks, Stephanie M and Chiang, Theodore and Duraine, Lita and Erdin, Serkan and Yuan, Bo and Shao, Yunru and Moussallem, Elie and Lamperti, Costanza and Donati, Maria A and Smith, Joshua D and McLaughlin, Heather M and Eng, Christine M and Walkiewicz, Magdalena and Xia, Fan and Pippucci, Tommaso and Magini, Pamela and Seri, Marco and Zeviani, Massimo and Hirano, Michio and Hunter, Jill V and Srour, Myriam and Zanigni, Stefano and Lewis, Richard Alan and Muzny, Donna M and Lotze, Timothy E and Boerwinkle, Eric and Gibbs, Richard A and Hickey, Scott E and Graham, Brett H and Yang, Yaping and Buhas, Daniela and Martin, Donna M and Potocki, Lorraine and Graziano, Claudio and Bellen, Hugo J and Lupski, James R} } @article {115, title = {Whole-Exome Sequencing in Familial Parkinson Disease.}, journal = {JAMA Neurol}, volume = {73}, year = {2016}, month = {2016 Jan}, pages = {68-75}, abstract = {

IMPORTANCE: Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors.

OBJECTIVE: To identify genetic variants contributing to disease risk in familial PD.

DESIGN, SETTING, AND PARTICIPANTS: A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD.

MAIN OUTCOMES AND MEASURES: Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design.

RESULTS: The 93 individuals from 32 families in the discovery cohort (49.5\% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6\% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing.

CONCLUSIONS AND RELEVANCE: TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.

}, keywords = {Adult, Aged, Cohort Studies, Exome, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Middle Aged, Parkinsonian Disorders, Protein-Tyrosine Kinases, Sequence Analysis, DNA, Tenascin}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2015.3266}, author = {Farlow, Janice L and Robak, Laurie A and Hetrick, Kurt and Bowling, Kevin and Boerwinkle, Eric and Coban-Akdemir, Zeynep H and Gambin, Tomasz and Gibbs, Richard A and Gu, Shen and Jain, Preti and Jankovic, Joseph and Jhangiani, Shalini and Kaw, Kaveeta and Lai, Dongbing and Lin, Hai and Ling, Hua and Liu, Yunlong and Lupski, James R and Muzny, Donna and Porter, Paula and Pugh, Elizabeth and White, Janson and Doheny, Kimberly and Myers, Richard M and Shulman, Joshua M and Foroud, Tatiana} } @article {198, title = {Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes.}, journal = {J Clin Invest}, volume = {125}, year = {2015}, month = {2015 Feb}, pages = {636-51}, abstract = {

Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65\% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be "transcriptomopathies" rather than cohesinopathies.

}, keywords = {Adolescent, Adult, Cell Cycle Proteins, Child, Child, Preschool, Chondroitin Sulfate Proteoglycans, Chromosomal Proteins, Non-Histone, Codon, Nonsense, De Lange Syndrome, Exome, Exonucleases, Gene Expression Profiling, Gene Expression Regulation, Genome-Wide Association Study, Heterozygote, Histone Deacetylases, Histone-Lysine N-Methyltransferase, Humans, Infant, Male, Myeloid-Lymphoid Leukemia Protein, Phenotype, Proteins, Repressor Proteins, Transcriptome}, issn = {1558-8238}, doi = {10.1172/JCI77435}, author = {Yuan, Bo and Pehlivan, Davut and Karaca, Ender and Patel, Nisha and Charng, Wu-Lin and Gambin, Tomasz and Gonzaga-Jauregui, Claudia and Sutton, V Reid and Yesil, G{\"o}zde and Bozdogan, Sevcan Tug and Tos, Tulay and Koparir, Asuman and Koparir, Erkan and Beck, Christine R and Gu, Shen and Aslan, Huseyin and Yuregir, Ozge Ozalp and Al Rubeaan, Khalid and Alnaqeb, Dhekra and Alshammari, Muneera J and Bayram, Yavuz and Atik, Mehmed M and Aydin, Hatip and Geckinli, B Bilge and Seven, Mehmet and Ulucan, Hakan and Fenercioglu, Elif and Ozen, Mustafa and Jhangiani, Shalini and Muzny, Donna M and Boerwinkle, Eric and Tuysuz, Beyhan and Alkuraya, Fowzan S and Gibbs, Richard A and Lupski, James R} }