@article {442, title = {Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 08 14}, pages = {73}, abstract = {

BACKGROUND: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder.

METHODS: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review.

RESULTS: We demonstrate greater than expected phenotypic heterogeneity, including 33\% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites.

CONCLUSIONS: Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified.

}, keywords = {Adolescent, Adult, CDC2 Protein Kinase, Child, Child, Preschool, Face, Female, Heart Defects, Congenital, Humans, Infant, Intellectual Disability, Male, Mutation, Phenotype, Syndrome}, issn = {1756-994X}, doi = {10.1186/s13073-017-0463-8}, author = {Bostwick, Bret L and McLean, Scott and Posey, Jennifer E and Streff, Haley E and Gripp, Karen W and Blesson, Alyssa and Powell-Hamilton, Nina and Tusi, Jessica and Stevenson, David A and Farrelly, Ellyn and Hudgins, Louanne and Yang, Yaping and Xia, Fan and Wang, Xia and Liu, Pengfei and Walkiewicz, Magdalena and McGuire, Marianne and Grange, Dorothy K and Andrews, Marisa V and Hummel, Marybeth and Madan-Khetarpal, Suneeta and Infante, Elena and Coban-Akdemir, Zeynep and Miszalski-Jamka, Karol and Jefferies, John L and Rosenfeld, Jill A and Emrick, Lisa and Nugent, Kimberly M and Lupski, James R and Belmont, John W and Lee, Brendan and Lalani, Seema 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 {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 {248, title = {De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 May 01}, pages = {784-9}, abstract = {

Clinical whole-exome sequencing (WES) for identification of mutations leading to Mendelian disease has been offered to the medical community since 2011. Clinically undiagnosed neurological disorders are the most frequent basis for test referral, and currently, approximately 25\% of such cases are diagnosed at the molecular level. To date, there are approximately 4,000 "known" disease-associated loci, and many are associated with striking dysmorphic features, making genotype-phenotype correlations relatively straightforward. A significant fraction of cases, however, lack characteristic dysmorphism or clinical pathognomonic traits and are dependent upon molecular tests for definitive diagnoses. Further, many molecular diagnoses are guided by recent gene-disease association discoveries. Hence, there is a critical interplay between clinical testing and research leading to gene-disease association discovery. Here, we describe four probands, all of whom presented with hypotonia, intellectual disability, global developmental delay, and mildly dysmorphic facial features. Three of the four also had sleep apnea. Each was a simplex case without a remarkable family history. Using WES, we identified AHDC1 de novo truncating mutations that most likely cause this genetic syndrome.

}, keywords = {Child, Child, Preschool, DNA-Binding Proteins, Exome, Female, Humans, Infant, Intellectual Disability, Language Development Disorders, Male, Muscle Hypotonia, Mutation, Sleep Apnea Syndromes, Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.04.006}, author = {Xia, Fan and Bainbridge, Matthew N and Tan, Tiong Yang and Wangler, Michael F and Scheuerle, Angela E and Zackai, Elaine H and Harr, Margaret H and Sutton, V Reid and Nalam, Roopa L and Zhu, Wenmiao and Nash, Margot and Ryan, Monique M and Yaplito-Lee, Joy and Hunter, Jill V and Deardorff, Matthew A and Penney, Samantha J and Beaudet, Arthur L and Plon, Sharon E and Boerwinkle, Eric A and Lupski, James R and Eng, Christine M and Muzny, Donna M and Yang, Yaping and Gibbs, Richard A} } @article {211, title = {Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Nov 06}, pages = {579-83}, abstract = {

5q31.3 microdeletion syndrome is characterized by neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay, and the minimal critical deletion interval harbors three genes. We describe 11 individuals with clinical features of 5q31.3 microdeletion syndrome and de novo mutations in PURA, encoding transcriptional activator protein Pur-α, within the critical region. These data implicate causative PURA mutations responsible for the severe neurological phenotypes observed in this syndrome.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Animals, Base Sequence, Caenorhabditis elegans, Chromosome Deletion, Chromosome Mapping, Chromosomes, Human, Pair 5, DNA-Binding Proteins, Humans, Molecular Sequence Data, Muscle Hypotonia, Mutation, Seizures, Sequence Analysis, DNA, Syndrome, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.09.014}, author = {Lalani, Seema R and Zhang, Jing and Schaaf, Christian P and Brown, Chester W and Magoulas, Pilar and Tsai, Anne Chun-Hui and El-Gharbawy, Areeg and Wierenga, Klaas J and Bartholomew, Dennis and Fong, Chin-To and Barbaro-Dieber, Tina and Kukolich, Mary K and Burrage, Lindsay C and Austin, Elise and Keller, Kory and Pastore, Matthew and Fernandez, Fabio and Lotze, Timothy and Wilfong, Angus and Purcarin, Gabriela and Zhu, Wenmiao and Craigen, William J and McGuire, Marianne and Jain, Mahim and Cooney, Erin and Azamian, Mahshid and Bainbridge, Matthew N and Muzny, Donna M and Boerwinkle, Eric and Person, Richard E and Niu, Zhiyv and Eng, Christine M and Lupski, James R and Gibbs, Richard A and Beaudet, Arthur L and Yang, Yaping and Wang, Meng C and Xia, Fan} }