Clinical report: A patient with a late diagnosis of cerebrotendinous xanthomatosis and a response to treatment
We report this case to illustrate the potential benefits of therapy in patients with CTX who have advanced disease at the time of diagnosis. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - June 7, 2017 Category: Genetics & Stem Cells Authors: Ahmad Alhariri, Katherine Hamilton, Vikash Oza, Kelly Cordoro, Nara L. Sobreira, Mary Malloy, Anne Slavotinek Tags: CLINICAL REPORT Source Type: research

A heterozygous microdeletion of 20p12.2 –3 encompassing PROKR2 and BMP2 in a patient with congenital hypopituitarism and growth hormone deficiency
In conclusion, congenital hypopituitarism can be present in individuals with a 20p12.3 deletion, observed with incomplete penetrance. Array CGH may be a useful investigation in select cases of early onset growth hormone deficiency, and patients with deletions within this region should be evaluated for pituitary hormone deficiencies. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - June 6, 2017 Category: Genetics & Stem Cells Authors: Samuel J. H. Parsons, Neville B. Wright, Emma Burkitt ‐Wright, Mars S. Skae, Phillip G. Murray Tags: CLINICAL REPORT Source Type: research

Neuroradiographic findings in 22q11.2 deletion syndrome
22q11.2 deletion syndrome (22q11.2DS) is a common genetic disorder with enormous phenotypic heterogeneity. Despite the established prevalence of developmental and neuropsychiatric issues in this syndrome, its neuroanatomical correlates are not as well understood. A retrospective chart review was performed on 111 patients diagnosed with 22q11.2DS. Of the 111 patients, 24 with genetically confirmed 22q11.2 deletion and brain MRI or MRA were included in this study. The most common indications for imaging were unexplained developmental delay (6/24), seizures of unknown etiology (5/24), and unilateral weakness (3/24). More than...
Source: American Journal of Medical Genetics Part A - June 3, 2017 Category: Genetics & Stem Cells Authors: Lauren A. Bohm, Tom C. Zhou, Tyler J. Mingo, Sarah L. Dugan, Richard J. Patterson, James D. Sidman, Brianne B. Roby Tags: ORIGINAL ARTICLE Source Type: research

A novel mutation in GMPPA in siblings with apparent intellectual disability, epilepsy, dysmorphism, and autonomic dysfunction
In this study, we report a female proband with achalasia, alacrima, hypohydrosis, apparent intellectual disability, seizures, microcephaly, esotropia, and craniofacial dysmorphism. Exome sequencing identified a previously unreported homozygous c.853+1G>A variant in GMPPA in the proband and her affected sister. Their unaffected parents were heterozygous, and unaffected brother homozygous wild type for this variant. Lymphoblast cells from the affected sisters showed complete loss of the GMPPA protein by Western blotting, and increased levels of GDP‐mannose in lymphoblasts on high performance liquid chromatography. Based...
Source: American Journal of Medical Genetics Part A - June 2, 2017 Category: Genetics & Stem Cells Authors: Wendy A. Gold, Nara Sobreira, Elsa Wiame, Alexandre Marbaix, Emile Van Schaftingen, Patricia Franzka, Lisa G. Riley, Lisa Worgan, Christian A. H übner, John Christodoulou, Lesley C. Adès Tags: CLINICAL REPORT Source Type: research

A heritable microduplication encompassing TBL1XR1 causes a genomic sister ‐disorder for the 3q26.32 microdeletion syndrome
Recently, a new syndrome with intellectual disability (ID) and dysmorphic features due to deletions or point mutations within the TBL1XR1 gene located in the chromosomal band 3q26.32 has been described (MRD41, OMIM 616944). One recurrent point mutation in the TBL1XR1 gene has been identified as the cause of Pierpont syndrome (OMIM 602342), a distinct intellectual disability syndrome with plantar lipomatosis. In addition, different de novo point mutations in the TBL1XR1 gene have been found in patients with autism spectrum disorders (ASD) and intellectual disability. Here, we report four patients from two unrelated families...
Source: American Journal of Medical Genetics Part A - June 2, 2017 Category: Genetics & Stem Cells Authors: Vera Riehmer, Florian Erger, Peter Herkenrath, Saskia Seland, Miriam Jackels, Alfred Wiater, Raoul Heller, Bodo B. Beck, Christian Netzer Tags: ORIGINAL ARTICLE Source Type: research

A new diagnosis of Williams –Beuren syndrome in a 49‐year‐old man with severe bullous emphysema
Williams–Beuren syndrome (WBS) is a chromosomal microdeletion syndrome typically presenting with intellectual disability, a unique personality, a characteristic facial appearance, and cardiovascular disease. Several clinical features of WBS are thought to be due to haploinsufficiency of elastin (ELN), as the ELN locus is included within the WBS critical region at 7q11.23. Emphysema, a disease attributed to destruction of pulmonary elastic fibers, has been reported in patients without WBS who have pathogenic variants in ELN but only once (in one patient) in WBS. Here we report a second adult WBS patient with emphysema...
Source: American Journal of Medical Genetics Part A - June 2, 2017 Category: Genetics & Stem Cells Authors: Monica H. Wojcik, Nikkola Carmichael, Frederick R. Bieber, Daniel C. Wiener, Rachna Madan, Barbara R. Pober, Benjamin A. Raby Tags: CLINICAL REPORT Source Type: research

Variable expressivity of a likely pathogenic variant in KCNQ2 in a three ‐generation pedigree presenting with intellectual disability with childhood onset seizures
KCNQ2 has been reported as a frequent cause of autosomal dominant benign familial neonatal seizures. De novo likely pathogenic variants in KCNQ2 have been described in neonatal or early infantile onset epileptic encephalopathy patients. Here, we report a three‐generation family with six affected patients with a novel likely pathogenic variant (c.628C>T; p.Arg210Cys) in KCNQ2. Four family members, three adults and a child, presented with a childhood seizure onset with variability in the severity of seizures and response to treatment, intellectual disability (ID) as well as behavioral problems. The two youngest affected...
Source: American Journal of Medical Genetics Part A - June 1, 2017 Category: Genetics & Stem Cells Authors: Stacy Hewson, Klajdi Puka, Saadet Mercimek ‐Mahmutoglu Tags: CLINICAL REPORT Source Type: research

Growth charts for Australian children with achondroplasia
This study aimed to produce head circumference, height, weight, and BMI reference percentile curves for Australian children and adolescents with achondroplasia. Measurements of head circumference, height and weight taken at clinical visits were retrospectively extracted from the electronic medical record. Age was corrected for prematurity. Patients were excluded from head circumference analysis if they had significant neurosurgical complications and from the weight and BMI analysis when they had a clinical diagnosis of overweight. Measurements were available on 138 individuals (69 males and 69 females) taken between 1970 a...
Source: American Journal of Medical Genetics Part A - June 1, 2017 Category: Genetics & Stem Cells Authors: Louise Tofts, Sandeep Das, Felicity Collins, Karen L. O. Burton Tags: ORIGINAL ARTICLE Source Type: research

On the significance of craniosynostosis in a case of Kabuki syndrome with a concomitant KMT2D mutation and 3.2  Mbp de novo 10q22.3q23.1 deletion
We report here a boy with facial asymmetry due to combined premature synostosis of the right coronal and sagittal sutures as well as several symptoms reminiscent of Kabuki syndrome (KS). Our case supports previous observations and suggests that craniosynostosis is a part of the KS phenotype. The uniqueness of our case is the sporadic co‐occurrence of two genetic disorders, that is, a de novo frameshift variant in the KMT2D gene and a de novo 3.2 Mbp 10q22.3q23.1 deletion. Our findings emphasize the importance of the initial clinical assessment of children with craniosynostosis and that genomic and monogenic disord...
Source: American Journal of Medical Genetics Part A - June 1, 2017 Category: Genetics & Stem Cells Authors: Alexandra Topa, Lena Samuelsson, Lovisa Lovmar, G öran Stenman, Lars Kölby Tags: ORIGINAL ARTICLE Source Type: research

Co ‐occurrence of Jalili syndrome and muscular overgrowth
Jalili syndrome is a rare disorder inherited in an autosomal recessive pattern manifesting as a combination of cone‐rod dystrophy including progressive loss of visual acuity, color blindness, photophobia, and amelogenesis imperfecta with hypoplastic, immature, or hypocalcified dental enamel. It is caused by mutations in CNNM4, which encodes the ancient conserved domain protein 4. Here we report three brothers with Jalili syndrome and muscle overgrowth of the legs. Myopathic changes were found in needle electromyography. Mutational analysis showed in all three brothers a novel likely pathogenic homozygous missense substit...
Source: American Journal of Medical Genetics Part A - June 1, 2017 Category: Genetics & Stem Cells Authors: Anna Wawrocka, Joanna Walczak ‐Sztulpa, Magdalena Badura‐Stronka, Michal Owecki, Przemysław Kopczynski, Ewa Mrukwa‐Kominek, Anna Skorczyk‐Werner, Piotr Gasperowicz, Rafal Ploski, Maciej R. Krawczynski Tags: CLINICAL REPORT Source Type: research

Associated anomalies in cases with esophageal atresia
In conclusion the overall prevalence of associated anomalies, which was close to one in two cases, emphasizes the need for a thorough investigation of cases with EA. A routine screening for other anomalies may be considered in infants and in fetuses with EA. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - June 1, 2017 Category: Genetics & Stem Cells Authors: Claude Stoll, Yves Alembik, Beatrice Dott, Marie ‐Paule Roth Tags: ORIGINAL ARTICLE Source Type: research

Anthropometric charts and congenital anomalies in newborns with Down syndrome
The objectives of this study were to obtain updated neonatal measurements in French newborns with Down Syndrome (DS) according to their gestational age, and to assess the frequency and distribution of congenital anomalies. Data on congenital malformations, birth weight, birth length and birth occipito‐frontal circumference (OFC) according to the gestational age was gathered from 1,030 babies, born between 1980 and 2010. The mean gestational age was 38 weeks from the date of the last menstrual period (LMP) (range: 29–42 weeks). Repartition of complications was found to be similar to previous studies, with no differe...
Source: American Journal of Medical Genetics Part A - June 1, 2017 Category: Genetics & Stem Cells Authors: Clotilde Mircher, Jeanne Toulas, C écile Cieuta‐Walti, Isabelle Marey, Martine Conte, Laura González Briceño, Marie‐Laure Tanguy, Marie‐Odile Rethore, Aime Ravel Tags: ORIGINAL ARTICLE Source Type: research

Auditory and otologic profile of Alstr öm syndrome: Comprehensive single center data on 38 patients
Alström syndrome (AS) is a rare autosomal recessive ciliopathy caused by mutations in the ALMS1 gene. Hallmark characteristics include childhood onset of severe retinal degeneration, sensorineural hearing loss, obesity, insulin‐resistant diabetes, and cardiomyopathy. Here we comprehensively characterize the auditory and otologic manifestations in a prospective case series of 38 individuals, aged 1.7–37.9 years, with genetically confirmed AS. Hearing loss was preceded by retinal dystrophy in all cases, and had an average age of detection of 7.45 years (range 1.5–15). Audiometric assessments showed mean pu...
Source: American Journal of Medical Genetics Part A - June 1, 2017 Category: Genetics & Stem Cells Authors: Spencer Lindsey, Carmen Brewer, Olga Stakhovskaya, Hung Jeffrey Kim, Chris Zalewski, Joy Bryant, Kelly A. King, J ürgen K. Naggert, William A. Gahl, Jan D. Marshall, Meral Gunay‐Aygun Tags: ORIGINAL ARTICLE Source Type: research

Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome
We reported on two patients including the first prenatal case described so far, carrying a 2p15 deletion affecting two genes: XPO1 and part of USP34. Both patients shared similar features including facial dysmorphism and cerebral abnormalities. We considered the genes involved in the deleted segment to further understand the abnormal phenotype. The third case we described here was a 4‐year‐old boy with a heterozygous de novo 427 kb deletion encompassing BCL11A and PAPOLG at 2p16.1. He displayed speech delay, autistic traits, and motor stereotypies associated with brain structure abnormalities. We discuss the con...
Source: American Journal of Medical Genetics Part A - June 1, 2017 Category: Genetics & Stem Cells Authors: Jonathan L évy, Aurélie Coussement, Céline Dupont, Fabien Guimiot, Clarisse Baumann, Géraldine Viot, Sandrine Passemard, Yline Capri, Séverine Drunat, Alain Verloes, Eva Pipiras, Brigitte Benzacken, Jean‐Michel Dupont, Anne‐Claude Tabet Tags: ORIGINAL ARTICLE Source Type: research

Mandibulofacial dysostosis Bauru type: Refining the phenotype
Mandibulofacial dysostosis (MFD) Bauru type (OMIM 604830) is a rare genetic condition characterized mainly by malar hypoplasia, orofacial cleft, and micrognathia. Here, we describe the clinical and radiographic sings of 13 individuals (12 female and 1 male) from eight unrelated kindreds with MFD Bauru type, including four previously reported cases, treated at the Hospital for Rehabilitation of Craniofacial Anomalies. The clinical phenotype was characterized by severe underdevelopment of mandible, midface hypoplasia, orofacial cleft, bitemporal narrowing, mild upper eyelid down slanting, high nasal bridge, thick and everted...
Source: American Journal of Medical Genetics Part A - May 31, 2017 Category: Genetics & Stem Cells Authors: Priscila P. Moura, Nancy M. Kokitsu ‐Nakata, Marília S. Yatabe, Siulan Vendramini‐Pittoli, Pedro H. Hori, Maria L. Guion‐Almeida, Daniela G. Garib, Antonio Richieri‐Costa, Roseli M. Zechi‐Ceide Tags: ORIGINAL ARTICLE Source Type: research

Phenotypes and genotypes in individuals with SMC1A variants
SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A varian...
Source: American Journal of Medical Genetics Part A - May 26, 2017 Category: Genetics & Stem Cells Authors: Sylvia Huisman, Paul A. Mulder, Egbert Redeker, Ingrid Bader, Anne ‐Marie Bisgaard, Alice Brooks, Anna Cereda, Constanza Cinca, Dinah Clark, Valerie Cormier‐Daire, Matthew A. Deardorff, Karin Diderich, Mariet Elting, Anthonie van Essen, David Fitz Pat Tags: ORIGINAL ARTICLE Source Type: research

Presynaptic congenital myasthenic syndrome with a homozygous sequence variant in LAMA5 combines myopia, facial tics, and failure of neuromuscular transmission
We report here a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin alpha‐5 subunit gene (LAMA5). The variant c.8046C>T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had muscle weakness, myopia, and facial tics. Magnetic resonance imaging of brain showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation revealed 50% decrement of compound muscle action potential amplitudes and 250% facilitation immediately after exercise, E...
Source: American Journal of Medical Genetics Part A - May 25, 2017 Category: Genetics & Stem Cells Authors: Ricardo A. Maselli, Juan Arredondo, Jessica V ázquez, Jessica X. Chong, , Michael J. Bamshad, Deborah A. Nickerson, Marian Lara, Fiona Ng, Victoria L. Lo, Peter Pytel, Craig M. McDonald Tags: CLINICAL REPORT Source Type: research

Molybdenum cofactor deficiency: Identification of a patient with homozygote mutation in the MOCS3 gene
We describe the clinical presentation and 17 years follow up of a boy, born to consanguineous parents and presenting with intellectual disability (ID), autism, “marfanoid” dysmorphic features, and moderate abnormalities of sulfite metabolism compatible with molybdenum cofactor deficiency, but normal sulfite oxidase activity in cultured skin fibroblasts. Genomic exome analysis revealed a homozygous MOCS3 missense mutation, leading to a p.Ala257Thr substitution in the highly conserved ubiquitin‐like‐domain of the protein. MOCS3 is the third protein, besides MOCS1 and MOCS2, involved in the biosynthesis of the...
Source: American Journal of Medical Genetics Part A - May 25, 2017 Category: Genetics & Stem Cells Authors: Jan G. M. Huijmans, Rachel Schot, Johannis B. C. de Klerk, Monique Williams, Ren é F. M. de Coo, Marinus Duran, Frans W. Verheijen, Marjon van Slegtenhorst, Grazia M. S. Mancini Tags: ORIGINAL ARTICLE Source Type: research

In this issue
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 25, 2017 Category: Genetics & Stem Cells Tags: the AJMG SEQUENCE: Decoding News and Trends for the Medical Genetics Community by Deborah Levenson Source Type: research

Revisions to common rule regarding human research issued
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 25, 2017 Category: Genetics & Stem Cells Tags: the AJMG SEQUENCE: Decoding News and Trends for the Medical Genetics Community by Deborah Levenson Source Type: research

Reanalyzing exomes may be worthwhile
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 25, 2017 Category: Genetics & Stem Cells Tags: the AJMG SEQUENCE: Decoding News and Trends for the Medical Genetics Community by Deborah Levenson Source Type: research

Publication schedule for 2017
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 25, 2017 Category: Genetics & Stem Cells Tags: ISSUE INFORMATION Source Type: research

Table of Contents, Volume 173A, Number 6, June 2017
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 25, 2017 Category: Genetics & Stem Cells Tags: ISSUE INFORMATION Source Type: research

Cover Image, Volume 173A, Number 6, June 2017
The cover image, by Toshiki Takenouchi et al., is based on the Clinical Report Further evidence that a blepharophimosis syndrome phenotype is associated with a specific class of mutation in the ADNP gene, DOI: 10.1002/ajmg.a.38126. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 25, 2017 Category: Genetics & Stem Cells Authors: Toshiki Takenouchi, Tomoru Miwa, Yoshiaki Sakamoto, Yuri Sakaguchi, Tomoko Uehara, Takao Takahashi, Kenjiro Kosaki Tags: COVER IMAGE Source Type: research

4.7  Mb deletion encompassing TGFB2 associated with features of Loeys–Dietz syndrome and osteoporosis in adulthood
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 25, 2017 Category: Genetics & Stem Cells Authors: Harald Gaspar, Bernd Lutz, Kerstin Reicherter, Simon L ühl, Rita Taurman, Heinz Gabriel, Rolf E. Brenner, Guntram Borck Tags: RESEARCH LETTER Source Type: research

A tumor profile in Patau syndrome (trisomy 13)
Individuals with trisomic conditions like Down syndrome and Edwards syndrome are prone to certain types of malignancy. However, for Patau syndrome (constitutional trisomy 13), which occurs in 1/10,000–1/20,000 live births, the tumor profile has not been well characterized. An awareness of susceptibility to malignancies can improve care of affected individuals, as well as further our understanding of the contribution of trisomy to carcinogenesis. Therefore, we conducted an extensive review of the literature; we found 17 malignancies reported in individuals with Patau syndrome. These comprised eight embryonic tumors, t...
Source: American Journal of Medical Genetics Part A - May 25, 2017 Category: Genetics & Stem Cells Authors: Daniel Satg é, Motoi Nishi, Nicolas Sirvent, Michel Vekemans, Marie‐Pierre Chenard, Ann Barnes Tags: ORIGINAL ARTICLE Source Type: research

Haploinsufficiency of NR4A2 is associated with a neurodevelopmental phenotype with prominent language impairment
Non‐recurrent deletions in 2q24.1, minimally overlapping two genes, NR4A2 and GPD2, were recently described in individuals with language impairment and behavioral and cognitive symptoms. We herewith report on a female patient with a similar phenotype of severe language and mild cognitive impairment, in whom we identified a de novo deletion covering only NR4A2. NR4A2 encodes a transcription factor highly expressed in brain regions critical for speech and language and implicated in dopaminergic neuronal development. Our findings of a de novo deletion of NR4A2 in an individual with mild intellectual disability and prominent...
Source: American Journal of Medical Genetics Part A - May 24, 2017 Category: Genetics & Stem Cells Authors: Miriam S. Reuter, Mandy Krumbiegel, Gregor Schl üter, Arif B. Ekici, André Reis, Christiane Zweier Tags: CLINICAL REPORT Source Type: research

Obstructive sleep apnea in Down syndrome: Benefits of surgery and noninvasive respiratory support
Children with Down syndrome are at increased risk of obstructive sleep apnea (OSA). The aim of the study was to describe the management of OSA in a large cohort of children with Down syndrome. A retrospective analysis of sleep studies and consequent management was performed for all consecutive Down syndrome patients evaluated between September 2013 and April 2016. The data of 57 patients were analyzed: 51/53 had an interpretable overnight polygraphy and 4 the recording of nocturnal gas exchange. Mean age at baseline sleep study was 6.2 ± 5.9 years. Eighteen patients (32%) had prior upper airway surgery...
Source: American Journal of Medical Genetics Part A - May 24, 2017 Category: Genetics & Stem Cells Authors: Benjamin Dudoignon, Alessandro Amaddeo, Annick Frapin, Briac Thierry, Livio de Sanctis, Jorge Olmo Arroyo, Sonia Khirani, Brigitte Fauroux Tags: ORIGINAL ARTICLE Source Type: research

Discordant phenotypes in monozygotic twins with 16p11.2 microdeletions including the SH2B1 gene
A 200∼240 kb SH2B1‐containing deletion region on 16p11.2 is associated with early‐onset obesity and developmental delay. Here, we describe monozygotic twin brothers with discordant clinical presentations. Intrauterine fetal growth restriction was present in both twins. Additionally, twin A exhibited coarctation of aorta, left ventricular noncompaction, atrial septal defect, pericardial effusion, left hydronephrosis, and moderate developmental delay, whereas twin B exhibited single umbilical artery. Chromosome microarray analysis was performed on both twins and their parents. An identical 244 kb microd...
Source: American Journal of Medical Genetics Part A - May 24, 2017 Category: Genetics & Stem Cells Authors: Lin Li, Linhuan Huang, Shaobin Lin, Yanmin Luo, Qun Fang Tags: CLINICAL REPORT Source Type: research

37th Annual David W. Smith Workshop on Malformations and Morphogenesis: Abstracts of the 2016 Annual Meeting
The 37th Annual David W. Smith Workshop on Malformations and Morphogenesis occurred on September 9th–14th, 2016 at the University of California—Los Angeles Conference Center in Lake Arrowhead, CA. The Workshop, which honors the legacy of David W. Smith, brought together clinicians and researchers interested in congenital malformations and their underlying mechanisms of morphogenesis. The Workshop highlighted five themes besides mechanisms of morphogenesis and New Syndromes: Neural Crestopathies, Mosaicism, Disorders of Skin Pigmentation, Therapies, and Ear Malformations and Hearing Loss. This Conference Report ...
Source: American Journal of Medical Genetics Part A - May 24, 2017 Category: Genetics & Stem Cells Authors: Kim M. Keppler ‐Noreuil, Julian A. Martinez‐Agosto, Louanne Hudgins, John C. Carey Tags: CONFERENCE REPORT Source Type: research

Renal anomalies and lymphedema distichiasis syndrome. A rare association?
Lymphedema distichiasis syndrome (LDS) is a rare, autosomal dominant genetic condition, characterized by lower limb lymphedema and distichiasis. Other associated features that have been reported include varicose veins, cleft palate, congenital heart defects, and ptosis. We update a previously reported family with a pathogenic variant in FOXC2 (c.412‐413insT) where five affected individuals from the youngest generation had congenital renal anomalies detected on prenatal ultrasound scan. These included four fetuses with hydronephrosis and one with bilateral renal agenesis. A further child with LDS had prominence of the lef...
Source: American Journal of Medical Genetics Part A - May 23, 2017 Category: Genetics & Stem Cells Authors: Gabriela E. Jones, Anna K. Richmond, Osric Navti, Hatem A. Mousa, Stephen Abbs, Edward Thompson, Sahar Mansour, Pradeep C. Vasudevan Tags: CLINICAL REPORT Source Type: research

Recurrent ATP2A2 p.(Pro602Leu) mutation differentiates Acrokeratosis verruciformis of Hopf from the allelic condition Darier disease
We report a family with AKV due to the p.(Pro602Leu) mutation and discuss implications for this recurrent mutation on knowledge of ATP2A2 structure and function. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 12, 2017 Category: Genetics & Stem Cells Authors: Anne Ronan, Angela Ingrey, Natalia Murray, Paul Chee Tags: CLINICAL REPORT Source Type: research

Adaptive and maladaptive functioning in Kleefstra syndrome compared to other rare genetic disorders with intellectual disabilities
Detailed neurobehavioural profiles are of major value for specific clinical management, but have remained underexposed in the population with intellectual disabilities (ID). This was traditionally classified based on IQ level only. Rapid advances in genetics enable etiology based stratification in the majority of patients, which reduces clinical heterogeneity. This paper illustrates that specific profiles can be obtained for rare syndromes with ID. Our main aim was to study (mal)adaptive functioning in Kleefstra Syndrome (KS) by comparing and contrasting our findings to three other subgroups: Koolen‐de Vries Syndrome, GA...
Source: American Journal of Medical Genetics Part A - May 12, 2017 Category: Genetics & Stem Cells Authors: Karlijn Vermeulen, Anneke de Boer, Joost G. E. Janzing, David A. Koolen, Charlotte W. Ockeloen, Marjolein H. Willemsen, Floor M. Verhoef, Patricia A. M. van Deurzen, Linde van Dongen, Hans van Bokhoven, Jos I. M. Egger, Wouter G. Staal, Tjitske Kleefstra Tags: ORIGINAL ARTICLE Source Type: research

Neuropsychological phenotypes of 76 individuals with Joubert syndrome evaluated at a single center
Joubert syndrome (JS) is a genetically heterogeneous ciliopathy characterized by hypo‐dysplasia of the cerebellar vermis, a distinct hindbrain/midbrain malformation (molar tooth sign), and intellectual disability. We evaluated the neuropsychological profiles of 76 participants with JS in the context of molecular genetics and clinical covariates. Evaluations included neuropsychological testing, structured parental interviews, DNA sequencing, brain magnetic resonance imaging (MRI), electroencephalography (EEG), ophthalmologic examination, and assessment for renal and hepatic disease. On average, participants manifested Ful...
Source: American Journal of Medical Genetics Part A - May 12, 2017 Category: Genetics & Stem Cells Authors: Angela C. Summers, Joseph Snow, Edythe Wiggs, Alexander G. Liu, Camilo Toro, Andrea Poretti, Wadih M. Zein, Brian P. Brooks, Melissa A. Parisi, Sara Inati, Dan Doherty, Meghana Vemulapalli, Jim C. Mullikin, , Thierry Vilboux, William A. Gahl, Meral Gunay Tags: ORIGINAL ARTICLE Source Type: research

Male child with somatic mosaic Osteopathia Striata with Cranial Sclerosis caused by a novel pathogenic AMER1 frameshift mutation
We report a case of a male child who has proven somatic mosaicism for OSCS associated with a novel pathogenic frameshift mutation, c.607_611delAGGCC (p.Arg203 fs) in AMER1. We describe the multisystemic clinical features which include macrocephaly with ventriculomegaly and requirement for ventriculoperitoneal shunt, cleft palate, and respiratory difficulties after birth requiring tracheostomy insertion, persistent patent ductus arteriosus, failure to thrive and gastrostomy insertion, growth retardation, ophthalmoplegia, kidney malformation, cryptorchidism, and developmental delay. The use of new technologies with ne...
Source: American Journal of Medical Genetics Part A - May 12, 2017 Category: Genetics & Stem Cells Authors: Jennifer Hague, Isabelle Delon, Kim Brugger, Howard Martin, Leanne Sparnon, Ingrid Simonic, Stephen Abbs, Soo ‐Mi Park Tags: CLINICAL REPORT Source Type: research

Diagnosis of CoPAN by whole exome sequencing: Waking up a sleeping tiger's eye
This report not only illustrates that WES is a powerful tool to elucidate the etiology of rare genetic diseases, but also identifies unique neuroimaging and metabolic findings that may be key features for an early diagnosis of CoPAN. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 10, 2017 Category: Genetics & Stem Cells Authors: Christina Evers, Angelika Seitz, Birgit Assmann, Thomas Opladen, Stephanie Karch, Katrin Hinderhofer, Martin Granzow, Nagarajan Paramasivam, Roland Eils, Nicolle Diessl, Claus R. Bartram, Ute Moog Tags: ORIGINAL ARTICLE Source Type: research

Artificial reproductive techniques and epigenetic alterations: Additional comments to the article by Arcos ‐Machancoses et al. ()
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 9, 2017 Category: Genetics & Stem Cells Authors: Antonio P érez‐Aytés, José V. Arcos‐Machancoses, Purificacion Marin Reina, M. Teresa Jimenez Busselo, Francisco Martínez Tags: RESEARCH LETTER Source Type: research

Left ventricular noncompaction cardiomyopathy in a patient with trisomy 13: A report and review of the literature
We described a patient with trisomy 13 who was diagnosed with LVNC‐dilated phenotype and died suddenly, as well as two additional patients with LVNC. All three patients had chronic heart failure without congenital heart disease and were treated with diuretics. To manage trisomy 13 with or without congenital heart disease, cardiac disease such as LVNC may present at any ages, and therefore cardiac evaluation should be considered as a part of their appropriate management. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 9, 2017 Category: Genetics & Stem Cells Authors: Anri Hayashi, Tomohiro Kumada, Fumihito Nozaki, Ikuko Hiejima, Minoru Shibata, Takashi Kusunoki, Tatsuya Fujii Tags: CLINICAL REPORT Source Type: research

Homozygous microdeletion of the ERI1 and MFHAS1 genes in a patient with intellectual disability, limb abnormalities, and cardiac malformation
A male child, born from consanguineous parents and having intellectual disability, short stature, dysmorphic facial features, synpolydactyly, and cardiac malformations is reported. Chromosomal microarray analysis showed that the patient presents with an 8p23.1 homozygous deletion, containing the microRNA miR‐4660, the exoribonuclease 1 (ERI1), and malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) genes. The microRNA miR‐4660 has no known function. MFHAS1 is an immunomodulatory protein involved in Toll‐like receptor signaling, erythropoiesis, and cancer. ERI1 is a ribonuclease involved in RNA metabolism and...
Source: American Journal of Medical Genetics Part A - May 9, 2017 Category: Genetics & Stem Cells Authors: Nancy Choucair, Mariam Rajab, Andr é Mégarbané, Eliane Chouery Tags: CLINICAL REPORT Source Type: research

Kaposi sarcoma, oral malformations, mitral dysplasia, and scoliosis associated with 7q34 ‐q36.3 heterozygous terminal deletion
Chromosome 7 germline macrodeletions have been implicated in human congenital malformations and developmental delays. We herein report a novel heterozygous macrodeletion of 7q34‐q36.3 in a 16‐year‐old girl originally from West Indies. Similar to previously reported cases of germline chromosome 7q terminal deletions, our patient has dental malposition, and developmental (growth and intellectual) delay. Novel phenotypic features include endemic Kaposi sarcoma (KS), furrowed tongue, thoracolumbar scoliosis, and mild mitral valve dysplasia. The occurrence of human herpes virus 8‐driven KS, in a child otherwise normally...
Source: American Journal of Medical Genetics Part A - May 9, 2017 Category: Genetics & Stem Cells Authors: Carolyn C. Jackson, Alain Lef èvre‐Utile, Anne Guimier, Valérie Malan, Julie Bruneau, Antoine Gessain, Olivier Cassar, Jeanne Amiel, Aurélie Cobat, Vimel Rattina, Laurent Abel, Jean‐Laurent Casanova, Stéphane Blanche Tags: ORIGINAL ARTICLE Source Type: research

A comparison of the functional health of children with Costello syndrome in 1999 and in 2015
Costello Syndrome is a rare congenital condition characterized by failure‐to‐thrive, cardiac abnormalities, distinctive facial features, predisposition to malignant tumors, and developmental delay. In 1999, we analyzed the functional health in a cohort of 18 patients. Since then, a mutation in the HRAS gene has been found to be causative, medical management has been refined, and the level of awareness has increased. The purpose of this study is to compare the functional health outcomes from the 1999 cohort with data prospectively collected from a comparable cohort in 2015. The Pediatric Outcome Data Collection Instrume...
Source: American Journal of Medical Genetics Part A - May 9, 2017 Category: Genetics & Stem Cells Authors: Viviana Bompadre, Tressa Mattioli ‐Lewis, Walid K. Yassir, Michael J. Goldberg Tags: ORIGINAL ARTICLE Source Type: research

Sclerotic bone lesions in tuberous sclerosis complex: A genotype –phenotype study
The objective of this study is to characterize sclerotic bone lesions detected by chest CT in a large cohort of adult TSC patients and to correlate with genotype. Chest CT scans of 92 adult patients with a definite clinical diagnosis of TSC were reviewed. Sclerotic bone lesions were found in 82 cases (89%) and affected mainly the posterior vertebral elements. Patients without bone lesions had negative mutational studies of TSC1/TSC2 in 86%. Awareness of these lesions in TSC is important to avoid misdiagnosis with osteoblastic metastases. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 9, 2017 Category: Genetics & Stem Cells Authors: Susana Boronat, Ignasi Barber, Elizabeth Anne Thiele Tags: ORIGINAL ARTICLE Source Type: research

Acne conglobata in a long ‐term survivor with trisomy 13, accompanied by selective IgM deficiency
Trisomy 13 (T13) is a congenital chromosomal disorder that is usually fatal within 2 years of birth, and only a few patients have been reported to reach adolescence. Here, we report a male long‐term survivor of T13, currently 15 years of age, with a several‐year history of extensive acne conglobata (AC) with abscesses on the face and neck. Methicillin‐resistant Staphylococcus aureus was consistently isolated from the pustular lesions. Serum IgM levels were extremely low at 10 mg/dl. There were no abnormalities in neutrophil and total B cell number, or in serum IgA and IgG levels. Increased CD8+ T cell c...
Source: American Journal of Medical Genetics Part A - May 7, 2017 Category: Genetics & Stem Cells Authors: Chiyoko N. Inoue, Yoshiko Tanaka, Nobuko Tabata Tags: CLINICAL REPORT Source Type: research

Novel features of Helsmoortel –Van der Aa/ADNP syndrome in a boy with a known pathogenic mutation in the ADNP gene detected by exome sequencing
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 5, 2017 Category: Genetics & Stem Cells Authors: Chumei Li, Yongdong Wang, Marta Szybowska Tags: CORRESPONDENCE Source Type: research

Nomenclature and definition in asymmetric regional body overgrowth
We designate a novel term “isolated lateralized overgrowth” (ILO) for the findings previously described as “isolated hemihypertrophy” and “isolated hemihyperplasia.” ILO is defined as lateralized overgrowth in the absence of a recognized pattern of malformations, dysplasia, or morphologic variants. ILO is likely genetically heterogeneous. Further study is required to determine more of the underlying genetic etiologies and potential associations with currently unrecognized patterns of malformation. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 5, 2017 Category: Genetics & Stem Cells Authors: Jennifer M. Kalish, Leslie G. Biesecker, Frederic Brioude, Matthew A. Deardorff, Alessandra Di Cesare ‐Merlone, Todd Druley, Giovanni B. Ferrero, Pablo Lapunzina, Lidia Larizza, Saskia Maas, Marina Macchiaiolo, Eamonn R. Maher, Silvia Maitz, Julian A. M Tags: ORIGINAL ARTICLE Source Type: research

Response to: Milosavljevic et al. “Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature”
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 5, 2017 Category: Genetics & Stem Cells Authors: Blair Stevens, Anthony Johnson, Thomas Rowe, Rebecca Carter, Roopali Donepudi Tags: CORRESPONDENCE Source Type: research

6q25.1 (TAB2) microdeletion syndrome: Congenital heart defects and cardiomyopathy
In this study, we describe 13 newly identified individuals with microdeletions of chromosome 6q25.1 that involve TAB2. One of the patients in our study cohort has the smallest deletion yet reported, affecting only TAB2. These were compared to 27 other patients reported in the published literature or DECIPHER to have similar microdeletions, for a total study group of 40 patients. Our study shows that individuals with TAB2 deletions are predisposed to developing a primary cardiomyopathy with reduced systolic function, even in the absence of CHD. Our study cohort also shares a number of non‐cardiac phenotypic findings: char...
Source: American Journal of Medical Genetics Part A - May 2, 2017 Category: Genetics & Stem Cells Authors: Andrew Cheng, Mary Beth P. Dinulos, Whitney Neufeld ‐Kaiser, Jill Rosenfeld, McKenna Kyriss, Suneeta Madan‐Khetarpal, Hiba Risheg, Peter H. Byers, Yajuan J. Liu Tags: ORIGINAL ARTICLE Source Type: research

Correspondence to Gripp et al. nephroblastomatosis or Wilms tumor in a fourth patient with a somatic PIK3CA mutation
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 1, 2017 Category: Genetics & Stem Cells Authors: Floor A. M. Postema, Saskia M. J. Hopman, Matthew A. Deardorff, Johannes H. M. Merks, Raoul C. Hennekam Tags: CORRESPONDENCE Source Type: research

A mutation in GABRB3 associated with Dravet syndrome
In this study, we performed exome sequencing in six patients with SCN1A‐negative Dravet syndrome to identify other genes related to this disorder. In one affected individual, we detected a novel de novo heterozygous missense variant, c.695G>A, p.(Arg232Gln), in GABRB3, the gene encoding the β3‐subunit of the gamma‐aminobutyric acid type A (GABAA) receptor, which mediates inhibitory signaling within the central nervous system. In summary, the data in this study identify GABRB3 as a candidate gene for Dravet syndrome. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 1, 2017 Category: Genetics & Stem Cells Authors: Sy Vinh Le, Phan Hoang Truc Le, Thi Khanh Van Le, Thi Thuy Kieu Huynh, Thi Thu Hang Do Tags: ORIGINAL ARTICLE Source Type: research

A novel variant in MED12 gene: Further delineation of phenotype
We describe a 5‐year‐old male patient with intellectual disability and facial dysmorphism and a novel variant in MED12 gene identified by Whole Exome Sequencing. His dysmorphic facial features are distinct from the previously described phenotypes. With a strong genotype–phenotype correlation that is already known for MED12, this could be a new phenotype linked to MED12, thus expanding the phenotypic spectrum of MED12‐related disorders. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - May 1, 2017 Category: Genetics & Stem Cells Authors: Dhanya L. Narayanan, Shubha R. Phadke Tags: CLINICAL REPORT Source Type: research