@article {714, title = {Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita.}, journal = {Hum Mutat}, volume = {40}, year = {2019}, month = {2019 12}, pages = {2270-2285}, abstract = {

Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo-/akinesia and/or (neurogenic) AMC.

}, issn = {1098-1004}, doi = {10.1002/humu.23841}, author = {Frints, Suzanna G M and Hennig, Friederike and Colombo, Roberto and Jacquemont, Sebastien and Terhal, Paulien and Zimmerman, Holly H and Hunt, David and Mendelsohn, Bryce A and Korda{\ss}, Ulrike and Webster, Richard and Sinnema, Margje and Abdul-Rahman, Omar and Suckow, Vanessa and Fern{\'a}ndez-Ja{\'e}n, Alberto and van Roozendaal, Kees and Stevens, Servi J C and Macville, Merryn V E and Al-Nasiry, Salwan and van Gassen, Koen and Utzig, Norbert and Koudijs, Suzanne M and McGregor, Lesley and Maas, Saskia M and Baralle, Diana and Dixit, Abhijit and Wieacker, Peter and Lee, Marcus and Lee, Arthur S and Engle, Elizabeth C and Houge, Gunnar and Gradek, Gyri A and Douglas, Andrew G L and Longman, Cheryl and Joss, Shelagh and Velasco, Danita and Hennekam, Raoul C and Hirata, Hiromi and Kalscheuer, Vera M} } @article {543, title = {Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 Feb 01}, pages = {309-320}, abstract = {

Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in~vitro, and in~vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.12.015}, author = {Martinelli, Simone and Krumbach, Oliver H F and Pantaleoni, Francesca and Coppola, Simona and Amin, Ehsan and Pannone, Luca and Nouri, Kazem and Farina, Luciapia and Dvorsky, Radovan and Lepri, Francesca and Buchholzer, Marcel and Konopatzki, Raphael and Walsh, Laurence and Payne, Katelyn and Pierpont, Mary Ella and Vergano, Samantha Schrier and Langley, Katherine G and Larsen, Douglas and Farwell, Kelly D and Tang, Sha and Mroske, Cameron and Gallotta, Ivan and Di Schiavi, Elia and Della Monica, Matteo and Lugli, Licia and Rossi, Cesare and Seri, Marco and Cocchi, Guido and Henderson, Lindsay and Baskin, Berivan and Alders, Marielle and Mendoza-Londono, Roberto and Dupuis, Lucie and Nickerson, Deborah A and Chong, Jessica X and Meeks, Naomi and Brown, Kathleen and Causey, Tahnee and Cho, Megan T and Demuth, Stephanie and Digilio, Maria Cristina and Gelb, Bruce D and Bamshad, Michael J and Zenker, Martin and Ahmadian, Mohammad Reza and Hennekam, Raoul C and Tartaglia, Marco and Mirzaa, Ghayda M} } @article {359, title = {Kaufman oculo-cerebro-facial syndrome in a child with small and absent terminal phalanges and absent nails.}, journal = {J Hum Genet}, volume = {62}, year = {2017}, month = {2017 Apr}, pages = {465-471}, abstract = {

Kaufman oculo-cerebro-facial syndrome (KOS) is caused by recessive UBE3B mutations and presents with microcephaly, ocular abnormalities, distinctive facial morphology, low cholesterol levels and intellectual disability. We describe a child with microcephaly, brachycephaly, hearing loss, ptosis, blepharophimosis, hypertelorism, cleft palate, multiple renal cysts, absent nails, small or absent terminal phalanges, absent speech and intellectual disability. Syndromes that were initially considered include DOORS syndrome, Coffin-Siris syndrome and Dubowitz syndrome. Clinical investigations coupled with karyotype analysis, array-comparative genomic hybridization, exome and Sanger sequencing were performed to characterize the condition in this child. Sanger sequencing was negative for the DOORS syndrome gene TBC1D24 but exome sequencing identified a homozygous deletion in UBE3B (NM_183415:c.3139_3141del, p.1047_1047del) located within the terminal portion of the HECT domain. This finding coupled with the presence of characteristic features such as brachycephaly, ptosis, blepharophimosis, hypertelorism, short palpebral fissures, cleft palate and developmental delay allowed us to make a diagnosis of KOS. In conclusion, our findings highlight the importance of considering KOS as a differential diagnosis for patients under evaluation for DOORS syndrome and expand the phenotype of KOS to include small or absent terminal phalanges, nails, and the presence of hallux varus and multicystic dysplastic kidneys.

}, keywords = {Abnormalities, Multiple, Adult, Carrier Proteins, Child, Child, Preschool, Diagnosis, Differential, Eczema, Eye Abnormalities, Face, Facies, Female, Growth Disorders, Hand Deformities, Congenital, Humans, Intellectual Disability, Karyotype, Limb Deformities, Congenital, Male, Microcephaly, Micrognathism, Mutation, Neck, Pathology, Molecular, Sequence Analysis, DNA, Ubiquitin-Protein Ligases}, issn = {1435-232X}, doi = {10.1038/jhg.2016.151}, author = {Kariminejad, Ariana and Ajeawung, Norbert Fonya and Bozorgmehr, Bita and Dionne-Laporte, Alexandre and Molidperee, Sirinart and Najafi, Kimia and Gibbs, Richard A and Lee, Brendan H and Hennekam, Raoul C and Campeau, Philippe M} } @article {281, title = {The genetic basis of DOORS syndrome: an exome-sequencing study.}, journal = {Lancet Neurol}, volume = {13}, year = {2014}, month = {2014 Jan}, pages = {44-58}, abstract = {

BACKGROUND: Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals.

METHODS: Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR.

FINDINGS: 26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis.

INTERPRETATION: Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24.

FUNDING: US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.

}, keywords = {Adolescent, Carrier Proteins, Child, Child, Preschool, Craniofacial Abnormalities, Exome, Female, Hand Deformities, Congenital, Hearing Loss, Sensorineural, Humans, Infant, Intellectual Disability, Internationality, Male, Nails, Malformed, Phenotype, Sequence Analysis, DNA, Young Adult}, issn = {1474-4465}, doi = {10.1016/S1474-4422(13)70265-5}, author = {Campeau, Philippe M and Kasperaviciute, Dalia and Lu, James T and Burrage, Lindsay C and Kim, Choel and Hori, Mutsuki and Powell, Berkley R and Stewart, Fiona and F{\'e}lix, T{\^e}mis Maria and van den Ende, Jenneke and Wisniewska, Marzena and Kayserili, H{\"u}lya and Rump, Patrick and Nampoothiri, Sheela and Aftimos, Salim and Mey, Antje and Nair, Lal D V and Begleiter, Michael L and De Bie, Isabelle and Meenakshi, Girish and Murray, Mitzi L and Repetto, Gabriela M and Golabi, Mahin and Blair, Edward and Male, Alison and Giuliano, Fabienne and Kariminejad, Ariana and Newman, William G and Bhaskar, Sanjeev S and Dickerson, Jonathan E and Kerr, Bronwyn and Banka, Siddharth and Giltay, Jacques C and Wieczorek, Dagmar and Tostevin, Anna and Wiszniewska, Joanna and Cheung, Sau Wai and Hennekam, Raoul C and Gibbs, Richard A and Lee, Brendan H and Sisodiya, Sanjay M} } @article {319, title = {Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Nov}, pages = {1249-54}, abstract = {

Elevated transforming growth factor (TGF)-β signaling has been implicated in the pathogenesis of syndromic presentations of aortic aneurysm, including Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). However, the location and character of many of the causal mutations in LDS intuitively imply diminished TGF-β signaling. Taken together, these data have engendered controversy regarding the specific role of TGF-β in disease pathogenesis. Shprintzen-Goldberg syndrome (SGS) has considerable phenotypic overlap with MFS and LDS, including aortic aneurysm. We identified causative variation in ten individuals with SGS in the proto-oncogene SKI, a known repressor of TGF-β activity. Cultured dermal fibroblasts from affected individuals showed enhanced activation of TGF-β signaling cascades and higher expression of TGF-β-responsive genes relative to control cells. Morpholino-induced silencing of SKI paralogs in zebrafish recapitulated abnormalities seen in humans with SGS. These data support the conclusions that increased TGF-β signaling is the mechanism underlying SGS and that high signaling contributes to multiple syndromic presentations of aortic aneurysm.

}, keywords = {Animals, Aortic Aneurysm, Arachnodactyly, Cells, Cultured, Craniosynostoses, DNA-Binding Proteins, Fibroblasts, Humans, Loeys-Dietz Syndrome, Marfan Syndrome, Mice, Mutation, Phenotype, Phosphorylation, Proto-Oncogene Proteins, Signal Transduction, Transforming Growth Factor beta, Zebrafish}, issn = {1546-1718}, doi = {10.1038/ng.2421}, author = {Doyle, Alexander J and Doyle, Jefferson J and Bessling, Seneca L and Maragh, Samantha and Lindsay, Mark E and Schepers, Dorien and Gillis, Elisabeth and Mortier, Geert and Homfray, Tessa and Sauls, Kimberly and Norris, Russell A and Huso, Nicholas D and Leahy, Dan and Mohr, David W and Caulfield, Mark J and Scott, Alan F and Destr{\'e}e, Anne and Hennekam, Raoul C and Arn, Pamela H and Curry, Cynthia J and Van Laer, Lut and McCallion, Andrew S and Loeys, Bart L and Dietz, Harry C} }