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American Journal of Medical Genetics. Part A

Leonie A Menke, Thatjana Gardeitchik, Peter Hammond, Ketil R Heimdal, Gunnar Houge, Sophia B Hufnagel, Jianling Ji, Stefan Johansson, Sarina G Kant, Esther Kinning, Eyby L Leon, Ruth Newbury-Ecob, Stefano Paolacci, Rolph Pfundt, Nicola K Ragge, Tuula Rinne, Claudia Ruivenkamp, Sulagna C Saitta, Yu Sun, Marco Tartaglia, Paulien A Terhal, Anthony J van Essen, Magnus D Vigeland, Bing Xiao, Raoul C Hennekam
In 2016, we described that missense variants in parts of exons 30 and 31 of CREBBP can cause a phenotype that differs from Rubinstein-Taybi syndrome (RSTS). Here we report on another 11 patients with variants in this region of CREBBP (between bp 5,128 and 5,614) and two with variants in the homologous region of EP300. None of the patients show characteristics typical for RSTS. The variants were detected by exome sequencing using a panel for intellectual disability in all but one individual, in whom Sanger sequencing was performed upon clinical recognition of the entity...
February 20, 2018: American Journal of Medical Genetics. Part A
Hailey Pinz, Louise C Pyle, Dong Li, Kosuke Izumi, Cara Skraban, Jennifer Tarpinian, Stephen R Braddock, Aida Telegrafi, Kristin G Monaghan, Elaine Zackai, Elizabeth J Bhoj
Myelin Regulatory Factor (MYRF) is a transcription factor that has previously been associated with the control of the expression of myelin-related genes. However, it is highly expressed in human tissues and mouse embryonic tissues outside the nervous system such as the stomach, lung, and small intestine. It has not previously been reported as a cause of any Mendelian disease. We report here two males with Scimitar syndrome [MIM 106700], and other features including penoscrotal hypospadias, cryptorchidism, pulmonary hypoplasia, tracheal anomalies, congenital diaphragmatic hernia, cleft spleen, thymic involution, and thyroid fibrosis...
February 15, 2018: American Journal of Medical Genetics. Part A
Samantha N Hartin, Waheeda A Hossain, Nicolette Weisensel, Merlin G Butler
Prader-Willi syndrome (PWS) is a complex genetic imprinting disorder characterized by childhood obesity, short stature, hypogonadism/hypogenitalism, hypotonia, cognitive impairment, and behavioral problems. Usually PWS occurs sporadically due to the loss of paternally expressed genes on chromosome 15 with the majority of individuals having the 15q11-q13 region deleted. Examples of familial PWS have been reported but rarely. To date 13 families have been reported with more than one child with PWS and without a 15q11-q13 deletion secondary to a chromosome 15 translocation, inversion, or uniparental maternal disomy 15...
February 13, 2018: American Journal of Medical Genetics. Part A
Yuri A Zarate, Constance L Smith-Hicks, Carol Greene, Mary-Alice Abbott, Victoria M Siu, Amy R U L Calhoun, Arti Pandya, Chumei Li, Elizabeth A Sellars, Julie Kaylor, Katherine Bosanko, Louisa Kalsner, Alice Basinger, Anne M Slavotinek, Hazel Perry, Margarita Saenz, Marta Szybowska, Louise C Wilson, Ajith Kumar, Caroline Brain, Meena Balasubramanian, Holly Dubbs, Xilma R Ortiz-Gonzalez, Elaine Zackai, Quinn Stein, Cynthia M Powell, Samantha Schrier Vergano, Allison Britt, Angela Sun, Wendy Smith, E Martina Bebin, Jonathan Picker, Amelia Kirby, Hailey Pinz, Hannah Bombei, Sonal Mahida, Julie S Cohen, Ali Fatemi, Hilary J Vernon, Rebecca McClellan, Leah R Fleming, Brittney Knyszek, Michelle Steinraths, Cruz Velasco Gonzalez, Anita E Beck, Katie L Golden-Grant, Alena Egense, Aditi Parikh, Chantalle Raimondi, Brad Angle, William Allen, Suzanna Schott, Adi Algrabli, Nathaniel H Robin, Joseph W Ray, David B Everman, Michael J Gambello, Wendy K Chung
SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing...
February 13, 2018: American Journal of Medical Genetics. Part A
Nuriye Dinckan, Renqian Du, Zeynep C Akdemir, Yavuz Bayram, Shalini N Jhangiani, Harsha Doddapaneni, Jianhong Hu, Donna M Muzny, Yeliz Guven, Oya Aktoren, Hulya Kayserili, Eric Boerwinkle, Richard A Gibbs, Jennifer E Posey, James R Lupski, Zehra O Uyguner, Ariadne Letra
Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common craniofacial abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c...
February 13, 2018: American Journal of Medical Genetics. Part A
Andrea Accogli, Fadi F Hamdan, Chantal Poulin, Christina Nassif, Guy A Rouleau, Jacques L Michaud, Myriam Srour
Adaptor protein complex-4 (AP-4) is a heterotetrameric protein complex which plays a key role in vesicle trafficking in neurons. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been recently associated with an autosomal recessive phenotype, consisting of spastic tetraplegia, and intellectual disability (ID). The overlapping clinical picture among individuals carrying mutations in any of these genes has prompted the terms "AP-4 deficiency syndrome" for this clinically recognizable phenotype...
February 12, 2018: American Journal of Medical Genetics. Part A
Terri P McVeigh, Jonathan A Soye, Emma Gordon, Sally A Lynch
Congenital anomalies of the upper limbs are rare and etiologically heterogeneous. Herein, we report a male infant with non-syndromic bilateral Type Vb ulnar longitudinal dysplasia with radiohumeral synostosis (apparent humeral bifurcation), and bilateral oligo-ectro-syndactyly who was born following an uncomplicated pregnancy, with no maternal use of prescription or illicit medication. Array CGH (60,000 probes) and chromosomal breakage analysis (DEB) were normal. Similar appearances have been reported in children exposed to thalidomide or cocaine, but sporadic patients have also been reported without a prior history of exposure to known teratogens...
February 10, 2018: American Journal of Medical Genetics. Part A
Ricardo Lima do Nascimento, Eduardo E Castilla, Maria da Graça Dutra, Iêda M Orioli
We compared Brazilian oral cleft (OC) frequencies between the population-based Brazilian System of Live Birth (SINASC) and the hospital-based Latin American Collaborative Study of Congenital Malformations (ECLAMC), trying to understand the paucity of cleft of lip and palate (CLP) in the first system. SINASC uses the International Classification of Disease version 10 (ICD-10) for congenital defects coding, ECLAMC uses ICD-8 with modifications. In SINASC, the CLP frequency was 1.7 per 10,000 (95% confidence limits 1...
February 9, 2018: American Journal of Medical Genetics. Part A
Mariana Del Pino, Rosario Ramos Mejía, Virginia Fano
Achondroplasia is the most common form of inherited disproportionate short stature. We report leg length, sitting height, and body proportion curves for achondroplasia. Seven centile format of sitting height, leg length, sitting height/leg length ratio, sitting height/height ratio, and head circumference/height ratio were estimated by the LMS method. The Q-test was applied to assess the goodness of fit. For comparison, centiles of sitting height and leg length were graphed using Argentine national growth references for achondroplasia and non-achondroplasia populations...
February 9, 2018: American Journal of Medical Genetics. Part A
Gerald F Cox
An important challenge in rare disease clinical trials is to demonstrate a clinically meaningful and statistically significant response to treatment. Selecting the most appropriate and sensitive efficacy endpoints for a treatment trial is part art and part science. The types of endpoints should align with the stage of development (e.g., proof of concept vs. confirmation of clinical efficacy). The patient characteristics and disease stage should reflect the treatment goal of improving disease manifestations or preventing disease progression...
February 9, 2018: American Journal of Medical Genetics. Part A
Wenmiao Zhu, Jianli Li, Stella Chen, Jinglan Zhang, Francesco Vetrini, Alicia Braxton, Christine M Eng, Yaping Yang, Fan Xia, Kory L Keller, Leila Okinaka-Hu, Chung Lee, J Lloyd Holder, Weimin Bi
SHANK3 encodes for a scaffolding protein that links neurotransmitter receptors to the cytoskeleton and is enriched in postsynaptic densities of excitatory synapses. Deletions or mutations in one copy of the SHANK3 gene cause Phelan-McDermid syndrome, also called 22q13.3 deletion syndrome, a neurodevelopmental disorder with common features including global developmental delay, absent to severely impaired language, autistic behavior, and minor dysmorphic features. By whole exome sequencing, we identified two de novo novel variants including one frameshift pathogenic variant and one missense variant of unknown significance in a 14-year-old boy with delayed motor milestones, delayed language acquisition, autism, intellectual disability, ataxia, progressively worsening spasticity of the lower extremities, dysmorphic features, short stature, microcephaly, failure to thrive, chronic constipation, intrauterine growth restriction, and bilateral inguinal hernias...
February 9, 2018: American Journal of Medical Genetics. Part A
Carole Samango-Sprouse, Emily Stapleton, Selena Chea, Patrick Lawson, Teresa Sadeghin, Chris Cappello, Leo de Sonneville, Sophie van Rijn
47,XXY (KS) occurs in 1:650 male births, though less than 25% are ever identified. We assessed stability of neurocognitive features across diverse populations and quantified factors mediating outcome. Forty-four boys from the Netherlands (NL) and 54 boys from the United States (US) participated. The Wechsler Intelligence Scales assessed intellectual functioning; the ANT program evaluated cognitive function; and the CBCL assessed behavioral functioning. ANOVA was used for group comparisons. Hierarchical regressions assessed variance explained by each independent variable: parental education, timing of diagnosis, testosterone, age, and nationality...
February 9, 2018: American Journal of Medical Genetics. Part A
Wendy N Nembhard, Xinyu Tang, Jingyun Li, Stewart L MacLeod, Joseph Levy, Gerald B Schaefer, Charlotte A Hobbs
The association between conotruncal heart defects (CTHDs) and maternal genetic and environmental exposures is well studied. However, little is known about paternal genetic or environmental exposures and risk of CTHDs. We assessed the effect of paternal genetic variants in the folate, homocysteine, and transsulfuration pathways on risk of CTHDs in offspring. We utilized National Birth Defects Prevention Study data to conduct a family-based case only study using 616 live-born infants with CTHDs, born October 1997-August 2008...
February 5, 2018: American Journal of Medical Genetics. Part A
Christina Bergqvist, Bilal Abdallah, Divina-Justina Hasbani, Ossama Abbas, Abdul Ghani Kibbi, Lamiaa Hamie, Mazen Kurban, Nelly Rubeiz
Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects (CHILD syndrome) is a rare X-linked dominant genodermatosis caused by mutations in the NAD(P) dependent steroid dehydrogenase-like protein gene. Its defect leads to accumulation of toxic metabolic intermediates upstream from the pathway block and to the deficiency of bulk cholesterol, probably leading to altered keratinocyte membrane function, resulting in the phenotype seen in CHILD syndrome. Symptomatic treatment using emollients and retinoids to reduce scaling has long been used until recently, whereby new therapeutic means based on the pathogenesis-targeted therapy have been developed...
February 2, 2018: American Journal of Medical Genetics. Part A
Martino Ruggieri, Andrea D Praticò, Rosario Caltabiano, Agata Polizzi
The earliest examples of neurofibromatosis (in this case type 1, NF1) can be traced in the Ebers Papyrus (Ancient Egypt, 1.500 B.C.), in a Hellenistic statuette (Smyrna, 323 B.C.), in the coinage of the Parthians kings (247 B.C.) and in some 13th century monks' drawings. These earlier examples are somewhat less well defined as compared to the most recent better defined reports credited as having NF1 including an Inca child mummy (1480-1650 AD), Ulisse Aldrovandi's homuncio ("Monstrorum Historia", 1592 A.D.) with mosaic NF1 or the illustrations seen in the 18th century "Buffon's Histoire Naturelle" and "Cruveilhier's Anatomie Pathologique du Corps Human"...
February 1, 2018: American Journal of Medical Genetics. Part A
Richard J Martin, Geoff Smith, James Hughes, Patrick J Morrison
No abstract text is available yet for this article.
February 1, 2018: American Journal of Medical Genetics. Part A
Daniel J Pomerantz, Sacha Ferdinandusse, Joy Cogan, David N Cooper, Tyler Reimschisel, Amy Robertson, Anna Bican, Tracy McGregor, Jackie Gauthier, David S Millington, Jaime L W Andrae, Michael R Tschannen, Daniel C Helbling, Wendy M Demos, Simone Denis, Ronald J A Wanders, John N Newman, Rizwan Hamid, John A Phillips
Mitochondrial NAD kinase deficiency (NADK2D, OMIM #615787) is a rare autosomal recessive disorder of NADPH biosynthesis that can cause hyperlysinemia and dienoyl-CoA reductase deficiency (DECRD, OMIM #616034). NADK2 deficiency has been reported in only three unrelated patients. Two had severe, unremitting disease; one died at 4 months and the other at 5 years of age. The third was a 10 year old female with CNS anomalies, ataxia, and incoordination. In two cases mutations in NADK2 have been demonstrated. Here, we report the fourth known case, a 15 year old female with normal intelligence and a mild clinical and biochemical phenotype presumably without DECRD...
February 1, 2018: American Journal of Medical Genetics. Part A
Toshiki Takenouchi, Tomoko Uehara, Kenjiro Kosaki, Seiji Mizuno
Recently, in a cohort study with "overgrowth syndrome with intellectual disability," five subjects were reported to have de novo heterozygous truncating variants in HIST1H1E, which encodes linker histone H 1.4. However, their growth pattern appeared complex that four out of five patients had a decreasing height percentile over time, and three of these patients began with above-average heights but exhibited reductions to average heights or below when they were older. Herein, we report a female patient with intellectual disability and distinctive facial features including a wide nasal bridge and prominent cheek bones...
January 31, 2018: American Journal of Medical Genetics. Part A
Alexandre Fabre, Laetitia-Marie Petit, Lars F Hansen, Anne V Wewer, Clothilde Esteve, Charlène Chaix, Patrice Bourgeois, Catherine Badens, Anders Paerregaard
Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare congenital enteropathy with seven main clinical features: intractable diarrhea of infancy, hair abnormalities, intrauterine growth restriction (IUGR), facial dysmorphism, immune dysfunction, and liver and skin abnormalities. SD/THE is caused by mutations in TTC37 or SKIV2L, two genes encoding components of the human SKI complex. To date, approximately 50 SD/THE patients have been described with a wide spectrum of mutations, and only one recurrent mutation has been identified in independent families...
January 31, 2018: American Journal of Medical Genetics. Part A
Laila Alrakaf, Mohammed A Al-Owain, Maryam Busehail, Maha A Alotaibi, Dorota Monies, Hesham M Aldhalaan, Amal Alhashem, Zuhair N Al-Hassnan, Zuhair A Rahbeeni, Fathiya Al Murshedi, Nadia Al Ani, Almundher Al-Maawali, Niema A Ibrahim, Firdous M Abdulwahab, Maysoon Alsagob, Mais O Hashem, Wafaa Ramadan, Mohamed Abouelhoda, Brian F Meyer, Namik Kaya, Sateesh Maddirevula, Fowzan S Alkuraya
Temtamy syndrome is a syndromic form of intellectual disability characterized by ocular involvement, epilepsy and dysgenesis of the corpus callosum. After we initially mapped the disease to C12orf57, we noted a high carrier frequency of an ancient startloss founder mutation [c.1A>G; p.M1?] in our population, and variable phenotypic expressivity in newly identified cases. This study aims to combine 33 previously published patients with 23 who are described here for the first time to further delineate the phenotype of this syndrome...
January 31, 2018: American Journal of Medical Genetics. Part A
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