@article {575, title = {De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 02 07}, pages = {246-259}, abstract = {

SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Using trio-based exome sequencing, we here identify de novo SOX4 heterozygous missense variants in four children who share developmental delay, intellectual disability, and mild facial and digital morphological abnormalities. SOX4 is highly expressed in areas of active neurogenesis in human fetuses, and sox4 knockdown in Xenopus embryos diminishes brain and whole-body size. The SOX4 variants cluster in the highly conserved, SOX family-specific HMG domain, but each alters a different residue. In silico tools predict that each variant affects a distinct structural feature of this DNA-binding domain, and functional assays demonstrate that these SOX4 proteins carrying these variants are unable to bind DNA in~vitro and transactivate SOX reporter genes in cultured cells. These variants are not found in the gnomAD database of individuals with presumably normal development, but 12 other SOX4 HMG-domain missense variants~are recorded and all demonstrate partial to full activity in the reporter assay. Taken together, these findings point to specific SOX4 HMG-domain missense variants as the cause of a characteristic human neurodevelopmental disorder associated with mild facial and digital dysmorphism.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Animals, Child, Child, Preschool, Coffin-Lowry Syndrome, Cohort Studies, Conserved Sequence, DNA, Female, Heterozygote, HMG-Box Domains, Humans, Male, Mutation, Missense, Neurodevelopmental Disorders, SOXC Transcription Factors, Transcriptional Activation, Xenopus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.12.014}, author = {Zawerton, Ash and Yao, Baojin and Yeager, J Paige and Pippucci, Tommaso and Haseeb, Abdul and Smith, Joshua D and Wischmann, Lisa and K{\"u}hl, Susanne J and Dean, John C S and Pilz, Daniela T and Holder, Susan E and McNeill, Alisdair and Graziano, Claudio and Lefebvre, V{\'e}ronique} } @article {227, title = {Exome sequencing identifies a recurrent de novo ZSWIM6 mutation associated with acromelic frontonasal dysostosis.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Aug 07}, pages = {235-40}, abstract = {

Acromelic frontonasal dysostosis (AFND) is a rare disorder characterized by distinct craniofacial, brain, and limb malformations, including frontonasal dysplasia, interhemispheric lipoma, agenesis of the corpus callosum, tibial hemimelia, preaxial polydactyly of the feet, and intellectual disability. Exome sequencing of one trio and two unrelated probands revealed the same heterozygous variant (c.3487C>T [p. Arg1163Trp]) in a highly conserved protein domain of ZSWIM6; this variant has not been seen in the 1000 Genomes data, dbSNP, or the Exome Sequencing Project. Sanger validation of the three trios confirmed that the variant was de novo and was also present in a fourth isolated proband. In situ hybridization of early zebrafish embryos at 24 hr postfertilization (hpf) demonstrated telencephalic expression of zswim6 and onset of midbrain, hindbrain, and retinal expression at 48 hpf. Immunohistochemistry of later-stage mouse embryos demonstrated tissue-specific expression in the derivatives of all three germ layers. qRT-PCR expression analysis of osteoblast and fibroblast cell lines available from two probands was suggestive of Hedgehog pathway activation, indicating that the ZSWIM6 mutation associated with AFND may lead to the craniofacial, brain and limb malformations through the disruption of Hedgehog signaling.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Animals, Base Sequence, Craniofacial Abnormalities, DNA Mutational Analysis, DNA-Binding Proteins, Exome, Face, Hedgehog Proteins, Humans, Intellectual Disability, Limb Deformities, Congenital, Mandibulofacial Dysostosis, Mice, Molecular Sequence Data, Mutation, Protein Structure, Tertiary, Zebrafish, Zinc Fingers}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.07.008}, author = {Smith, Joshua D and Hing, Anne V and Clarke, Christine M and Johnson, Nathan M and Perez, Francisco A and Park, Sarah S and Horst, Jeremy A and Mecham, Brig and Maves, Lisa and Nickerson, Deborah A and Cunningham, Michael L} } @article {256, title = {Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 May 01}, pages = {734-44}, abstract = {

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83\%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82\%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher{\textquoteright}s exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.

}, keywords = {Abnormalities, Multiple, Arachnodactyly, Arthrogryposis, Blepharophimosis, Child, Child, Preschool, Cleft Palate, Clubfoot, Connective Tissue Diseases, Contracture, Exome, Female, Hand Deformities, Congenital, Humans, Ion Channels, Male, Mutation, Ophthalmoplegia, Pedigree, Retinal Diseases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.03.015}, author = {McMillin, Margaret J and Beck, Anita E and Chong, Jessica X and Shively, Kathryn M and Buckingham, Kati J and Gildersleeve, Heidi I S and Aracena, Mariana I and Aylsworth, Arthur S and Bitoun, Pierre and Carey, John C and Clericuzio, Carol L and Crow, Yanick J and Curry, Cynthia J and Devriendt, Koenraad and Everman, David B and Fryer, Alan and Gibson, Kate and Giovannucci Uzielli, Maria Luisa and Graham, John M and Hall, Judith G and Hecht, Jacqueline T and Heidenreich, Randall A and Hurst, Jane A and Irani, Sarosh and Krapels, Ingrid P C and Leroy, Jules G and Mowat, David and Plant, Gordon T and Robertson, Stephen P and Schorry, Elizabeth K and Scott, Richard H and Seaver, Laurie H and Sherr, Elliott and Splitt, Miranda and Stewart, Helen and Stumpel, Constance and Temel, Sehime G and Weaver, David D and Whiteford, Margo and Williams, Marc S and Tabor, Holly K and Smith, Joshua D and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} } @article {307, title = {Mutations in KCTD1 cause scalp-ear-nipple syndrome.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Apr 04}, pages = {621-6}, abstract = {

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2α (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. The identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Branchio-Oto-Renal Syndrome, Ear, External, Ectodermal Dysplasia, Exome, Female, Humans, Hypospadias, Male, Molecular Sequence Data, Muscle Hypotonia, Mutation, Missense, Nipples, Pedigree, Phenotype, Protein Structure, Tertiary, Repressor Proteins, Scalp, Sequence Homology, Amino Acid}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.03.002}, author = {Marneros, Alexander G and Beck, Anita E and Turner, Emily H and McMillin, Margaret J and Edwards, Matthew J and Field, Michael and de Macena Sobreira, Nara Lygia and Perez, Ana Beatriz A and Fortes, Jose A R and Lampe, Anne K and Giovannucci Uzielli, Maria Luisa and Gordon, Christopher T and Plessis, Ghislaine and Le Merrer, Martine and Amiel, Jeanne and Reichenberger, Ernst and Shively, Kathryn M and Cerrato, Felecia and Labow, Brian I and Tabor, Holly K and Smith, Joshua D and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} }