“Lowe syndrome: A particularly severe phenotype without clinical kidney involvement”
This report, however, argues this association and suggests that kidney dysfunction may partially explain the growth deficiency and bone abnormalities, but other still undefined factors might have a potential impact. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - December 1, 2017 Category: Genetics & Stem Cells Authors: Abdalla Etesam, El ‐Beheiry Ahmed, Dieterich Klaus, Thevenon Julien, Fauré Julien, Rendu John Tags: CLINICAL REPORT Source Type: research

Therapy development in Huntington disease: From current strategies to emerging opportunities
Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder in which patients typically present with uncontrolled involuntary movements and subsequent cognitive decline. In 1993, a CAG trinucleotide repeat expansion in the coding region of the huntingtin (HTT) gene was identified as the cause of this disorder. This extended CAG repeat results in production of HTT protein with an expanded polyglutamine tract, leading to pathogenic HTT protein conformers that are resistant to protein turnover, culminating in cellular toxicity and neurodegeneration. Research into the mechanistic basis of HD has high...
Source: American Journal of Medical Genetics Part A - December 1, 2017 Category: Genetics & Stem Cells Authors: Audrey S. Dickey, Albert R. La Spada Tags: RESEARCH REVIEW Source Type: research

Phelan ‐McDermid syndrome and cancer predisposition: The value of a karyotype
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - December 1, 2017 Category: Genetics & Stem Cells Authors: Kent D. McKelvey, Carol J. Trana, Jill Kelsay, Jeffrey Sawyer, Jeffrey Clothier Tags: RESEARCH LETTER Source Type: research

Biallelic mutations in LARS2 can cause Perrault syndrome type 2 with neurologic symptoms
Perrault syndrome represents a genetically heterogeneous disorder characterized by sensorineural hearing loss in males and females and ovarian dysfunction in females. Causative genes include HARS2, HSD17B4, CLPP, C10orf2, and LARS2. Some patients with Perrault syndrome exhibit neurologic features including learning disability, cerebellar ataxia, and peripheral neuropathy and are classified as type 2 and are clinically separate from those without neurological symptoms other than a hearing loss (type 1). To date, all reported patients with LARS2 mutations (15 patients in 8 families) have been classified as type 1. Here, we r...
Source: American Journal of Medical Genetics Part A - December 1, 2017 Category: Genetics & Stem Cells Authors: Rika Kosaki, Reiko Horikawa, Eriko Fujii, Kenjiro Kosaki Tags: CLINICAL REPORT Source Type: research

Incomplete penetrance, variable expressivity, or dosage insensitivity in four families with directly transmitted unbalanced chromosome abnormalities
The direct transmission of microscopically visible unbalanced chromosome abnormalities (UBCAs) is rare and usually has phenotypic consequences. Here we report four families in which a normal phenotype was initially found in one or more family members. Each UBCA was interpreted with regard to overlapping examples and factors previously associated with transmitted imbalances including incidental ascertainment, low gene density, benign copy number variation (CNV) content, and gene relatedness. A 4.56 Mb deletion of 8p23.1‐p23.2 was thought to be causal in the affected proband but showed incomplete penetrance in her m...
Source: American Journal of Medical Genetics Part A - December 1, 2017 Category: Genetics & Stem Cells Authors: Mark S. Bateman, Morag N. Collinson, David J. Bunyan, Amanda L. Collins, Philippa Duncan, Rachel Firth, Victoria Harrison, Tessa Homfray, Shuwen Huang, Beth Kirk, Katherine L. Lachlan, Viv K. Maloney, John C. K. Barber Tags: ORIGINAL ARTICLE Source Type: research

Riboflavin transporter deficiency mimicking mitochondrial myopathy caused by complex II deficiency
We report two new patients whose clinical and biochemical features were mimicking mitochondrial myopathy. Patient 1 is an 8‐year‐old male with global developmental delay, axial and appendicular hypotonia, ataxia, and sensorineural hearing loss. His muscle biopsy showed complex II deficiency and ragged red fibers consistent with mitochondrial myopathy. Whole exome sequencing revealed a homozygous likely pathogenic variant in SLC52A2 (c.917G>A; p.Gly306Glu). Patient 2 is a 14‐month‐old boy with global developmental delay, respiratory insufficiency requiring ventilator support within the first year of life. His mus...
Source: American Journal of Medical Genetics Part A - November 30, 2017 Category: Genetics & Stem Cells Authors: Graeme A. M. Nimmo, Resham Ejaz, Dawn Cordeiro, Peter Kannu, Saadet Mercimek ‐Andrews Tags: CLINICAL REPORT Source Type: research

Clinical and molecular characterization of an emerging chromosome 22q13.31 microdeletion syndrome
We describe a patient showing neurodevelopmental disorders, dysmorphic features, and multiple congenital anomalies in which SNP array analysis revealed an interstitial 3.15 Mb de novo microdeletion in the 22q13.31 region encompassing 21 RefSeq genes and seven non‐coding microRNAs. To perform an accurate phenotype characterization, clinical features observed in previously reported cases of 22q13.31 microdeletions were reviewed and compared to those observed in our patient. To the best of our knowledge, this is the first time that a comparison between patients carrying overlapping 22q13.31 deletions has been done. This com...
Source: American Journal of Medical Genetics Part A - November 28, 2017 Category: Genetics & Stem Cells Authors: Pietro Palumbo, Maria Accadia, Maria P. Leone, Teresa Palladino, Raffaella Stallone, Massimo Carella, Orazio Palumbo Tags: CLINICAL REPORT Source Type: research

Cognitive and behavioral phenotype of children with pseudohypoparathyroidism type 1A
Pseudohypoparathyroidism 1A (PHP1A) is a rare, genetic disorder. Most patients with PHP1A have cognitive impairment but this has not been systematically studied. We hypothesized that children with PHP1A would have lower intelligent quotient (IQ) scores than controls. To evaluate cognition and behavior, we prospectively enrolled children with PHP1A, one unaffected sibling (when available) and controls matched on BMI/age/gender/race. Evaluations included cognitive and executive function testing. Parents completed questionnaires on behavior and executive function. We enrolled 16 patients with PHP1A, 8 unaffected siblings, and...
Source: American Journal of Medical Genetics Part A - November 28, 2017 Category: Genetics & Stem Cells Authors: Katia M. Perez, Evon B. Lee, Sachini Kahanda, Jessica Duis, Monica Reyes, Harald J üppner, Ashley H. Shoemaker Tags: ORIGINAL ARTICLE Source Type: research

Oligonephronia and Wolf ‐Hirschhorn syndrome: A further observation
We describe a case of a male 9 years old children with WHS proteinuria and hypertension. Laboratory data showed creatinine 1.05 mg/dl, GFR 65.9 ml/min/1.73 m2, cholesterol 280 mg/dl, triglyceride 125 mg/dl with electrolytes in the normal range. Urine collection showed protein 2.72 g/L with a urine protein/creatinine ratio (UP/UCr ratio) of 4.2 and diuresis of 1,100 ml. Renal ultrasound showed reduced kidney dimensions with diffusely hyperechogenic cortex and poorly visualized pyramids. Renal biopsy showed oligonephronia with focal segmental glomerulosclerosis associated with...
Source: American Journal of Medical Genetics Part A - November 28, 2017 Category: Genetics & Stem Cells Authors: Antonio Gatto, Pietro Ferrara, Chiara Leoni, Roberta Onesimo, Marcella Zollino, Francesco Emma, Giuseppe Zampino Tags: CLINICAL REPORT Source Type: research

Clinical and genetic characterization of AP4B1 ‐associated SPG47
The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by degeneration of the corticospinal and spinocerebellar tracts leading to progressive spasticity. One subtype, spastic paraplegia type 47 (SPG47 or HSP‐AP4B1), is due to bi‐allelic loss‐of‐function mutations in the AP4B1 gene. AP4B1 is a subunit of the adapter protein complex 4 (AP‐4), a heterotetrameric protein complex that regulates the transport of membrane proteins. Since 2011, 11 individuals from six families with AP4B1 mutations have been reported, nine of whom had homozygous mutations and were from consanguineou...
Source: American Journal of Medical Genetics Part A - November 28, 2017 Category: Genetics & Stem Cells Authors: Darius Ebrahimi ‐Fakhari, Chi Cheng, Kira Dies, Amelia Diplock, Danielle B. Pier, Conor S. Ryan, Brendan C. Lanpher, Jennifer Hirst, Wendy K. Chung, Mustafa Sahin, Elisabeth Rosser, Basil Darras, James T. Bennett, Tags: ORIGINAL ARTICLE Source Type: research

Rare FMR1 gene mutations causing fragile X syndrome: A review
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, typically due to CGG‐repeat expansions in the FMR1 gene leading to lack of expression. We identified a rare FMR1 gene mutation (c.413G>A), previously reported in a single patient and reviewed the literature for other rare FMR1 mutations. Our patient at 10 years of age presented with the classical findings of FXS including intellectual disability, autism, craniofacial findings, hyperextensibility, fleshy hands, flat feet, unsteady gait, and seizures but without the typical CGG‐repeat expansion. He had more features of FXS than the ...
Source: American Journal of Medical Genetics Part A - November 27, 2017 Category: Genetics & Stem Cells Authors: Adam F. Sitzmann, Robert T. Hagelstrom, Flora Tassone, Randi J. Hagerman, Merlin G. Butler Tags: ORIGINAL ARTICLE Source Type: research

Higher adaptive functioning and lower rate of psychotic comorbidity in married versus unmarried individuals with 22q11.2 deletion syndrome
22q11.2 deletion syndrome (22q11.2DS) is a relatively common genetic disorder. Due to improvement in pediatric care, affected individuals live into adulthood, some of whom marry or have committed relationships, and reproduce. The current study aimed to identify the factors that discriminate between married and unmarried adults with 22q11.2DS. In the presents study, 90 adults with 22q11.2DS (48 men/42 women), aged 29.8 ± 10.3 years, were included in the analysis. Psychiatric comorbidities, IQ score, and adaptive functioning were assessed using gold‐standard diagnostic tools. Demographic factors, marit...
Source: American Journal of Medical Genetics Part A - November 24, 2017 Category: Genetics & Stem Cells Authors: Mariela Mosheva, Stav Eyal, Omri Weisman, Reut Gilad, Yael Fishman, Ronnie Weinberger, Abraham Weizman, Doron Gothelf Tags: ORIGINAL ARTICLE Source Type: research

Structural malformations of the brain, eye, and pituitary gland in PHACE syndrome
PHACE syndrome is the association of segmental facial hemangiomas with congenital arterial, brain, cardiac, and ocular anomalies. Structural brain malformations affect 41–52% of PHACE patients and can be associated with focal neurologic deficits, developmental delays, and/or intellectual disability. To better characterize the spectrum of structural brain and other intracranial anomalies in PHACE syndrome, MRI scans of the head/neck were retrospectively reviewed in 55 patients from the PHACE Syndrome International Clinical Registry and Genetic Repository. All registry patients with a diagnosis of definite PHACE syndro...
Source: American Journal of Medical Genetics Part A - November 24, 2017 Category: Genetics & Stem Cells Authors: Jack E. Steiner, Garrett N. McCoy, Christopher P. Hess, William B. Dobyns, Denise W. Metry, Beth A. Drolet, Mohit Maheshwari, Dawn H. Siegel Tags: ORIGINAL ARTICLE Source Type: research

Higher adaptive functioning and lower rate of psychotic comorbidity in married versus unmarried individuals with 22q11.2 deletion syndrome
American Journal of Medical Genetics Part A, EarlyView. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 24, 2017 Category: Genetics & Stem Cells Authors: Mariela Mosheva , Stav Eyal , Omri Weisman , Reut Gilad , Yael Fishman , Ronnie Weinberger , Abraham Weizman , Doron Gothelf Source Type: research

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American Journal of Medical Genetics Part A, Ahead of Print. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 24, 2017 Category: Genetics & Stem Cells Source Type: research

Biallelic mutations in NALCN: Expanding the genotypic and phenotypic spectra of IHPRF1
Loss‐of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi‐allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi‐allelic splice site mutations, that is c.1267‐2A>G, derived from heterozygous parents, while Patient 2 had a partial materna...
Source: American Journal of Medical Genetics Part A - November 23, 2017 Category: Genetics & Stem Cells Authors: Toshiki Takenouchi, Mie Inaba, Tomoko Uehara, Takao Takahashi, Kenjiro Kosaki, Seiji Mizuno Tags: CLINICAL REPORT Source Type: research

Congenital limb deficiencies and major associated anomalies in Alberta for the years 1980 –2012
There is a wide range of the proportion of congenital anomalies associated with limb deficiencies reported in the literature. This variation is primarily attributed to methodology and classification differences. The distribution of associated anomalies among cases with congenital limb deficiencies in Alberta born between January 1, 1980 and December 31, 2012 is described. Of the 170 cases identified, most were live born (75.3%), male (61.8%), had longitudinal limb deficiencies (78.8%), and had associated anomalies outside the musculoskeletal system (77.6%). Significant associations between the preaxial longitudinal group a...
Source: American Journal of Medical Genetics Part A - November 23, 2017 Category: Genetics & Stem Cells Authors: Tanya Bedard, R. Brian Lowry, Barbara Sibbald, Susan Crawford, Gerhard N. Kiefer Tags: ORIGINAL ARTICLE Source Type: research

Single suture craniosynostosis: Identification of rare variants in genes associated with syndromic forms
We report RNA‐Sequencing results on a cohort of patients with single suture craniosynostosis and demonstrate significant enrichment of heterozygous, rare, and damaging variants among key craniosynostosis‐related genes. Genetic burden analysis identified a significant increase in damaging variants in ATR, EFNA4, ERF, MEGF8, SCARF2, and TGFBR2. Of 391 participants, 15% were found to have damaging and potentially causal variants in 29 genes. We observed transmission in 96% of the affected individuals, and thus penetrance, epigenetics, and oligogenic factors need to be considered when recommending genetic testing in patien...
Source: American Journal of Medical Genetics Part A - November 23, 2017 Category: Genetics & Stem Cells Authors: Christine M. Clarke, Vincent T. Fok, Jennifer A. Gustafson, Matthew D. Smyth, Andrew E. Timms, Chris D. Frazar, Joshua D. Smith, Craig B. Birgfeld, Amy Lee, Richard G. Ellenbogen, Joseph S. Gruss, Richard A. Hopper, Michael L. Cunningham Tags: ORIGINAL ARTICLE Source Type: research

Novel STRA6 null mutations in the original family described with Matthew –Wood syndrome
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 23, 2017 Category: Genetics & Stem Cells Authors: Francesca Pasutto, Frances Flinter, Anita Rauch, Andr é Reis Tags: RESEARCH LETTER Source Type: research

Temple syndrome as a differential diagnosis to Prader –Willi syndrome: Identifying three new patients
The two imprinting syndromes Temple syndrome (TS14) and Prader–Willi syndrome (PWS) share many features in infancy and childhood. TS14 is an important, yet often neglected, differential diagnosis to PWS. We wanted to assess the frequency of TS14 among patients tested for PWS. In all samples submitted to our lab for genetic PWS testing during 2014 and 2015, we consecutively conducted additional analyses for TS14. A total of 143 samples were included. The most frequent indications for testing were developmental delay, overweight, and hypotonia. For TS14 testing, we performed a methylation‐sensitive MLPA‐kit detecti...
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: Asgeir Lande, Mette Kroken, Kai Rabben, Lars Retterst øl Tags: CLINICAL REPORT Source Type: research

Orthopaedic manifestations within the 22q11.2 Deletion syndrome: A systematic review
American Journal of Medical Genetics Part A, EarlyView. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: Jelle F. Homans , Isabel N. Tromp , Dino Colo , Tom P. C. Schl össer , Moyo C. Kruyt , Vincent F. X. Deeney , Terrence B. Crowley , Donna M. McDonald‐McGinn , René M. Castelein Source Type: research

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American Journal of Medical Genetics Part A, Ahead of Print. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Source Type: research

Maternal inheritance of BDNF deletion, with phenotype of obesity and developmental delay in mother and child
This report highlights the maternal inheritance of a rare genetic cause of childhood obesity. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: Brooke E. Harcourt, Denise V. R. Bullen, Kung ‐Ting Kao, Daniella Tassoni, Erin J. Alexander, Trent Burgess, Susan M. White, Matthew A. Sabin Tags: CLINICAL REPORT Source Type: research

Marked yield of re ‐evaluating phenotype and exome/target sequencing data in 33 individuals with intellectual disabilities
This study confirmed the utility of exome sequencing in the diagnosis of ID/DD. Furthermore, re‐evaluation leads to a 15% improvement in diagnostic yield. Thus, to maximize the diagnostic yield of next‐generation sequencing (NGS), periodical re‐evaluation of the geno/phenotypic data of undiagnosed individuals is recommended by updating the OMIM annotation, applying new algorithms, reviewing the literature, sharing pheno/genotypic data, and re‐contacting patients. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: Bing Xiao, Wenjuan Qiu, Xing Ji, Xiaoqing Liu, Zhuo Huang, Huili Liu, Yanjie Fan, Yan Xu, Yu Liu, Hui Yie, Wei Wei, Hui Yan, Zhuwen Gong, Lixiao Shen, Yu Sun Tags: ORIGINAL ARTICLE Source Type: research

Summary of the first inaugural joint meeting of the International Consortium for scoliosis genetics and the International Consortium for vertebral anomalies and scoliosis, March 16 –18, 2017, Dallas, Texas
Scoliosis represents the most common musculoskeletal disorder in children and affects approximately 3% of the world population. Scoliosis is separated into two major phenotypic classifications: congenital and idiopathic. Idiopathic scoliosis is defined as a curvature of the spine of 10° or greater visualized on plane radiograph and does not have associated vertebral malformations (VM). “Congenital” scoliosis (CS) due to malformations in vertebrae is frequently associated with other birth defects. Recently, significant advances have been made in understanding the genetic basis of both conditions. There is ev...
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: Philip F. Giampietro, Olivier Pourquie, Cathy Raggio, Shiro Ikegawa, Peter D. Turnpenny, Ryan Gray, Sally L. Dunwoodie, Christina A. Gurnett, Benjamin Alman, Kenneth Cheung, Kenro Kusumi, Nancy Hadley ‐Miller, Carol A. Wise Tags: CONFERENCE REPORT Source Type: research

Orthopaedic manifestations within the 22q11.2 Deletion syndrome: A systematic review
The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion syndrome with an estimated prevalence of 1:4,000 live births. 22q11.2DS is known to have wide phenotypic variability, including orthopaedic manifestations. The purpose of this systematic review is to increase the awareness of orthopaedic manifestations associated with 22q11.2DS. This systematic review was performed according to the PRISMA Guidelines. Original epidemiological studies on the prevalence of orthopaedic manifestations within 22q11.2DS were systematically searched for in PubMed and EMBASE. The included articles were scored according to a ...
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: Jelle F. Homans, Isabel N. Tromp, Dino Colo, Tom P. C. Schl össer, Moyo C. Kruyt, Vincent F. X. Deeney, Terrence B. Crowley, Donna M. McDonald‐McGinn, René M. Castelein Tags: ORIGINAL ARTICLE Source Type: research

Tarsal ‐carpal coalition syndrome: Report of a novel missense mutation in NOG gene and phenotypic delineation
This report further delineates the phenotypic spectrum of this rare disorder with the addition of a new variant to the mutation spectrum. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: Aneek Das Bhowmik, Vijayalakshmi Salem Ramakumaran, Ashwin Dalal Tags: CLINICAL REPORT Source Type: research

Parental education accounts for variability in the IQs of probands with Down syndrome: A longitudinal study
Recent work has demonstrated that variability in probands’ phenotypes, including physical features, cognitive abilities, social functioning, and other developmental domains, is influenced by parental traits. Here we examine the role of parental education as a factor contributing to the variability of intelligence quotient (IQ) of offspring with trisomy 21. Participants were 43 probands with trisomy 21, aged 4–21 years of age, and their parents. Data were collected on parental education, and a bi‐parental mean education score (BMES) was calculated. Probands' cognitive abilities were assessed by the Stanford‐...
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: David W. Evans, Mirko Uljarevi ć Tags: RAPID COMMUNICATION Source Type: research

Response to: “In reply to: ‘Mast Cell Disorders in Ehlers–Danlos Syndrome’ (Jaime Vengoechea, Department of Human Genetics, Emory University)”
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: Suranjith L. Seneviratne, Anne Maitland, Lawrence B. Afrin Tags: CORRESPONDENCE Source Type: research

Less common underlying genetic diagnoses found in a cohort of 139 individuals surgically corrected for craniosynostosis
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: Benjamin R. Ittleman, Jasmine Mckissick, Katherine A. Bosanko, Eylem Ocal, Michael Golinko, Yuri A. Zarate Tags: RESEARCH LETTER Source Type: research

Discordant fetal phenotype of hypophosphatasia in two siblings
Hypophosphatasia (HPP) is an autosomal recessive metabolic disorder with impaired bone mineralization due to mutations in the ALPL gene. The genotype‐phenotype correlation of this disorder has been widely described. Here, we present two affected siblings, whose fetal phenotypes were discordant. A 31‐year‐old Japanese woman, G0P0, was referred to our institution because of fetal micromelia. After obstetric counseling, the pregnancy was terminated at 21 weeks’ gestation. Post‐mortem radiographs demonstrated severely defective mineralization of the skeleton. The calvarial, spinal, and tubular bones were mostly m...
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: Satoru Ikenoue, Kei Miyakoshi, Tomohiro Ishii, Yu Sato, Toshimitsu Otani, Yohei Akiba, Yoshifumi Kasuga, Daigo Ochiai, Tadashi Matsumoto, Yosuke Ichihashi, Yohei Matsuzaki, Kanako Tachikawa, Toshimi Michigami, Gen Nishimura, Kazushige Ikeda, Tomonobu Hase Tags: CLINICAL REPORT Source Type: research

FGFR1 disruption identified by whole genome sequencing in a male with a complex chromosomal rearrangement and hypogonadotropic hypogonadism
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: Kaori Yamoto, Shingo Okamoto, Yasuko Fujisawa, Maki Fukami, Hirotomo Saitsu, Tsutomu Ogata Tags: RESEARCH LETTER Source Type: research

MED13L loss ‐of‐function variants in two patients with syndromic Pierre Robin sequence
We report two unrelated patients with Pierre Robin sequence (PRS) and a strikingly similar combination of associated features. Whole exome sequencing was performed for both patients. No single gene containing likely pathogenic point mutations in both patients could be identified, but the finding of an essential splice site mutation in mediator complex subunit 13 like (MED13L) in one patient prompted the investigation of copy number variants in MED13L in the other, leading to the identification of an intragenic deletion. Disruption of MED13L, encoding a component of the Mediator complex, is increasingly recognized as the ca...
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: Christopher T. Gordon, Maya Chopra, Myriam Oufadem, Olivier Alibeu, Marc Bras, Nathalie Boddaert, Christine Bole ‐Feysot, Patrick Nitschké, Véronique Abadie, Stanislas Lyonnet, Jeanne Amiel Tags: CLINICAL REPORT Source Type: research

Kaufman oculocerebrofacial syndrome: Novel UBE3B mutations and clinical features in four unrelated patients
The “blepharophimosis‐mental retardation” syndromes (BMRS) consist of a group of clinically and genetically heterogeneous congenital malformation syndromes, where short palpebral fissures and intellectual disability associate with a distinct set of other morphological features. Kaufman oculocerebrofacial syndrome represents a rare and recently reevaluated entity within the BMR syndromes and is caused by biallelic mutations of UBE3B. Affected individuals typically show microcephaly, impaired somatic growth, gastrointestinal and genitourinary problems, ectodermal anomalies and a characteristic face with short, ...
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: R üstem Yilmaz, Katalin Szakszon, Anna Altmann, Umut Altunoglu, Leyli Senturk, Marianne McGuire, Olga Calabrese, Suneeta Madan‐Khetarpal, Lina Basel‐Vanagaite, Guntram Borck Tags: CLINICAL REPORT Source Type: research

Whole exome sequencing reveals a mutation in ARMC9 as a cause of mental retardation, ptosis, and polydactyly
We report on elucidation of molecular basis for syndromic ID associated with ptosis, polydactyly, and MRI features suggestive of Joubert syndrome using homozygosity mapping followed by exome sequencing. The analysis revealed a novel synonymous variation p.T293T (c.879G>A) which leads to a splicing defect in ARMC9 gene. The variant is present in conserved region of ARM domain of ARMC9 protein, which is predicted to form a platform for protein interaction. This domain is likely to be altered in patient due to splicing defect caused by this synonymous variation. Our report of variant in ARMC9 Leading to Joubert syndrome ph...
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: Anjana Kar, Shubha R. Phadke, Aneek Das Bhowmik, Ashwin Dalal Tags: ORIGINAL ARTICLE Source Type: research

Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme assay
Inherited metabolic disorders are traditionally diagnosed using broad and expensive panels of screening tests, often including invasive skin and muscle biopsy. Proponents of next‐generation genetic sequencing have argued that replacing these screening panels with whole exome sequencing (WES) would save money. Here, we present a complex patient in whom WES allowed diagnosis of GM1 gangliosidosis, caused by homozygous GLB1 mutations, resulting in β‐galactosidase deficiency. A 10‐year‐old girl had progressive neurologic deterioration, macular cherry‐red spot, and cornea verticillata. She had marked clinical imp...
Source: American Journal of Medical Genetics Part A - November 21, 2017 Category: Genetics & Stem Cells Authors: Kenneth A. Myers, Mark F. Bennett, Chung W. Chow, Susan M. Carden, Simone A. Mandelstam, Melanie Bahlo, Ingrid E. Scheffer Tags: CLINICAL REPORT Source Type: research

Expanding the neurodevelopmental phenotype of PURA syndrome
We describe 18 new individuals with heterozygous sequence variations in PURA. A neuromotor disorder starting with neonatal hyptonia, but ultimately allowing delayed progression to walking, was present in nearly all individuals. Congenital apnea was present in 56% during infancy, but all cases in this cohort resolved during the first year of life. Feeding difficulties were frequently reported, with gastrostomy tube placement required in 28%. Epilepsy was present in 50% of the subjects, including infantile spasms and Lennox–Gastaut syndrome. Skeletal complications were found in 39%. Disorders of gastrointestinal motili...
Source: American Journal of Medical Genetics Part A - November 18, 2017 Category: Genetics & Stem Cells Authors: Bo Hoon Lee, Margot R. F. Reijnders, Oluwatobi Abubakare, Emily Tuttle, Brynn Lape, Kelly Q. Minks, Christopher Stodgell, Loisa Bennetto, Jennifer Kwon, Chin ‐To Fong, Karen W. Gripp, Eric D. Marsh, Wendy E. Smith, Ahm M. Huq, Stephanie A. Coury, Wen‐ Tags: ORIGINAL ARTICLE Source Type: research

A model to characterize psychopathological features in adults with Prader ‐Willi syndrome
High prevalence of behavioral and psychiatric disorders in adults with Prader‐Willi Syndrome (PWS) has been reported in last few years. However, data are confusing and often contradictory. In this article, we propose a model to achieve a better understanding of the psychopathological features in adults with PWS. The study is based on clinical observations of 150 adult inpatients, males and females. Non‐parametric statistics were performed to analyse the association of psychopathological profiles with genotype, gender and age. We propose a model of psychiatric disorders in adults with PWS based on cognitive, emotional a...
Source: American Journal of Medical Genetics Part A - November 17, 2017 Category: Genetics & Stem Cells Authors: Denise Thuilleaux, Virginie Laurier, Pierre Copet, Julie Tricot, Genevi ève Demeer, Fabien Mourre, Maithé Tauber, Joseba Jauregi Tags: ORIGINAL ARTICLE Source Type: research

p.Arg69Trp in RNASEH2C is a founder variant in three Indian families with Aicardi –Goutières syndrome
Aicardi–Goutières syndrome is an early‐onset severe neurological disorder characterized by intracranial calcification, white matter abnormalities, hepatosplenomegaly, cerebrospinal fluid lymphocytosis, and elevated interferon‐α levels, thus mimicking congenital viral infections. It is a genetically heterogeneous condition and autosomal recessive and autosomal dominant forms with variations in seven genes known till date. Variations in RNASEH2C cause an autosomal recessive form of AGS. Here we report three Indian families with variant, c.205C>T (NM_032193.3, p.Arg69Trp) in RNASEH2C gene identified ...
Source: American Journal of Medical Genetics Part A - November 17, 2017 Category: Genetics & Stem Cells Authors: Malavika Hebbar, Anil Kanthi, Aroor Shrikiran, Snehal Patil, Mamta Muranjan, Febi Francis, Vishnu Bhat B, Katta M Girisha, Anju Shukla Tags: CLINICAL REPORT Source Type: research

Unique association of hypochondroplasia with craniosynostosis and cleft palate in a Mexican family
Hypochondroplasia (HCH) is a skeletal dysplasia caused by an abnormal function of the fibroblast growth factor receptor 3. Although believed to be relatively common, its prevalence and phenotype are not well established owing to its clinical, radiological, and genetic heterogeneity. Here we report on a molecularly proven HCH family with an affected father and two children. The siblings (male and female) with HCH also had craniosynostosis and cleft palate, respectively. The present report supports the conclusion that the full clinical spectrum of HCH is not completely delineated. It also suggests that secondary, as yet unkn...
Source: American Journal of Medical Genetics Part A - November 17, 2017 Category: Genetics & Stem Cells Authors: Ariadna Gonz ález‐del Angel, Alan Caro‐Contreras, Miguel Angel Alcántara‐Ortigoza, Sandra Ramos, Roberto Cruz‐Alcívar, Paola Moyers‐Pérez Tags: CLINICAL REPORT Source Type: research

Wieacker –Wolff syndrome with associated cleft palate in a female case
Wieacker–Wolff syndrome is a rare congenital syndrome with few reported cases in the current literature. It is traditionally described in males as an X‐linked recessive disorder associated with congenital contractures of the feet, progressive neurologic muscular atrophy, and intellectual delay caused by ZC4H2 mutations. The purpose of this paper is to present a female individual with a classic phenotype and cleft palate, a previously undescribed finding in this syndrome. Recent reports have demonstrated that females are rarely severely affected and phenotypic expression is difficult to predict [Zanzottera et al. ()...
Source: American Journal of Medical Genetics Part A - November 17, 2017 Category: Genetics & Stem Cells Authors: Natalie D. Godfrey, Samandar Dowlatshahi, Madelena M. Martin, Douglas M. Rothkopf Tags: CLINICAL REPORT Source Type: research

Family management of childhood chronic conditions: Does it make a difference if the child has an intellectual disability?
The purpose of this analysis was to assess the applicability of the Family Management Measure (FaMM) to families in which there was a child with an intellectual disability versus a chronic condition. Drawing on data from 571 parents of children with a chronic physical condition and 539 parents of children with Down syndrome, we compared the two groups across the six FaMM scales. After accounting for the covariate effects of race, ethnicity, family income, and child age, we found significant differences in four of the six FaMM scales, with parents of children with Down syndrome reporting a significantly more positive view o...
Source: American Journal of Medical Genetics Part A - November 16, 2017 Category: Genetics & Stem Cells Authors: Marcia Van Riper, George J. Knafl, Cecelia Roscigno, Kathleen A. Knafl Tags: ORIGINAL ARTICLE Source Type: research

A heterozygous mutation in RPGR associated with X ‐linked retinitis pigmentosa in a patient with Turner syndrome mosaicism (45,X/46,XX)
Turner syndrome with retinitis pigmentosa (RP) is rare, with only three cases reported based on clinical examination alone. We summarized the 4‐year follow‐up and molecular findings in a 28‐year‐old patient with Turner syndrome and the typical features of short stature and neck webbing, who also had X‐linked RP. Her main complaints were night blindness and progressive loss of vision since the age of 9 years. Ophthalmologic examination, optical coherent tomographic imaging, and visual electrophysiology tests showed classic manifestations of RP. The karyotype of peripheral blood showed mosaicism (45,X [72%]/46,XX[2...
Source: American Journal of Medical Genetics Part A - November 14, 2017 Category: Genetics & Stem Cells Authors: Qi Zhou, Fengxia Yao, Feng Wang, Hui Li, Rui Chen, Ruifang Sui Tags: CLINICAL REPORT Source Type: research

“Minimal” holoprosencephaly in a 14q deletion syndrome patient
We report on a patient with terminal deletion of the long arm of chromosome 14 displaying brain interhemispheric fusion limited to the midline anterior frontal cortex associated with hypoplastic corpus callosum and incomplete rotation of the left hippocampus in a clinical setting of motor and intellectual disability with poor language, and social behavior abnormalities with aggressiveness. Some possible correlations between clinical signs and symptoms and various aspects of the complex brain malformation are briefly discussed and compared with other known abnormalities of chromosome 14. The different neuropathology of the ...
Source: American Journal of Medical Genetics Part A - November 14, 2017 Category: Genetics & Stem Cells Authors: Elvio Della Giustina, Alessandro Iodice, Carlotta Spagnoli, Simona Giovannini, Daniele Frattini, Carlo Fusco, Giuseppe Gobbi, Marcella Zollino, Giovanni Neri Tags: CLINICAL REPORT Source Type: research

Clinical delineation of a subtype of frontonasal dysplasia with creased nasal ridge and upper limb anomalies: Report of six unrelated patients
In conclusion, we report six novel simplex individuals presenting with a specific frontonasal dysplasia entity associating recognizable facial features, limb and visceral malformations, and apparently normal development. The identification of discordant monozygotic twins supports the hypothesis of a mosaic disorder. Although previous patients have been reported, this is the first series, allowing delineation of a clinical subtype of frontonasal dysplasia, paving the way toward the identification of its molecular etiology. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 14, 2017 Category: Genetics & Stem Cells Authors: Daphn é Lehalle, Umut Altunoglu, Ange‐Line Bruel, Eric Arnaud, Patricia Blanchet, Jong‐Woo Choi, Julie Désir, Esra Kiliç, Damien Lederer, Lucile Pinson, Christel Thauvin‐Robinet, Amihood Singer, Julien Thevenon, Patrick Callier, Hulya Kayserili, Tags: NEW SYNDROME Source Type: research

In this issue
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 14, 2017 Category: Genetics & Stem Cells Tags: the AJMG SEQUENCE: Decoding News and Trends for the Medical Genetics Community by Deborah Levenson Source Type: research

Cryptographic Strategy Could Deliver Better Genomic Privacy
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 14, 2017 Category: Genetics & Stem Cells Tags: the AJMG SEQUENCE: Decoding News and Trends for the Medical Genetics Community by Deborah Levenson Source Type: research

Study Points to Value of Genetic Testing in Epilepsy
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - November 14, 2017 Category: Genetics & Stem Cells Tags: the AJMG SEQUENCE: Decoding News and Trends for the Medical Genetics Community by Deborah Levenson Source Type: research