Dolichol kinase deficiency (DOLK ‐CDG): Two new cases and expansion of phenotype
We report two female siblings with novel compound heterozygous mutations in DOLK: c.951C>A (p.Tyr317Ter) and c.1558A>G (p.Thr520Ala). Both patients presented in the neonatal period with severe ichthyosis, unusual distal digital constrictions and dilated cardiomyopathy which resulted in death. Histology of the skin showed lipid droplet accumulation in the stratum corneum and keratinocytes, which suggests defective epidermal lipid metabolism. These patients represent an earlier and more severe form of DOLK‐CDG (CDG‐1m) with a striking presentation at birth that expands the known phenotypic spectrum. (Source: Americ...
Source: American Journal of Medical Genetics Part A - August 17, 2017 Category: Genetics & Stem Cells Authors: Eric T. Rush, Craig V. Baker, William B. Rizzo 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 - August 17, 2017 Category: Genetics & Stem Cells Tags: the AJMG SEQUENCE: Decoding News and Trends for the Medical Genetics Community by Deborah Levenson Source Type: research

Few direct ‐to‐consumer test users receive genetic counseling
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - August 17, 2017 Category: Genetics & Stem Cells Tags: the AJMG SEQUENCE: Decoding News and Trends for the Medical Genetics Community by Deborah Levenson Source Type: research

Infants with cystic fibrosis still lag on some growth measures
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - August 17, 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 - August 17, 2017 Category: Genetics & Stem Cells Tags: ISSUE INFORMATION Source Type: research

Table of Contents, Volume 173A, Number 9, September 2017
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - August 17, 2017 Category: Genetics & Stem Cells Tags: ISSUE INFORMATION Source Type: research

Cover Image, Volume 173A, Number 9, September 2017
The cover image, by Paul Kruszka et al., is based on the Original Article Noonan Syndrome in Diverse Populations, DOI: 10.1002/ajmg.a.38362. Design Credit: Darryl Leja. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - August 17, 2017 Category: Genetics & Stem Cells Authors: Paul Kruszka, Antonio R. Porras, Yonit A. Addissie, Ang élica Moresco, Sofia Medrano, Gary T. K. Mok, Gordon K. C. Leung, Cedrik Tekendo‐Ngongang, Annette Uwineza, Meow‐Keong Thong, Premala Muthukumarasamy, Engela Honey, Ekanem N. Ekure, Ogochukwu J. Tags: COVER IMAGE Source Type: research

The role of IQSEC2 in syndromic intellectual disability: Narrowing the diagnostic odyssey
We report these cases to demonstrate the exhaustive work‐up prior to finding the changes in IQSEC2 gene, recommend that this gene be considered earlier in the diagnostic evaluation of individuals with global developmental delay, microcephaly, and severe, intractable epilepsy, and support the use of intellectual disability panels including IQSEC2 in the first‐line evaluation of these patients. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - August 17, 2017 Category: Genetics & Stem Cells Authors: Benjamin M. Helm, Zoe Powis, Carlos E. Prada, Olga L. Casasbuenas ‐Alarcon, Tonya Balmakund, G. B. Schaefer, Stephen G. Kahler, Julie Kaylor, Susan Winter, Yuri A. Zarate, Samantha A. Schrier Vergano Tags: CLINICAL REPORT Source Type: research

Diaphanospondylodysostosis and ischiospinal dysostosis, evidence for one disorder with variable expression in a patient who has survived to age 9 years
We report a patient with one deletion and one mutation of the BMPER gene who has features most consistent with DSD but who has survived to age 9 years. Survival suggests that DSD and ISD reflect a spectrum of severity of one disease process. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - August 17, 2017 Category: Genetics & Stem Cells Authors: Janet M. Legare, Kristin Seaborg, Jennifer Laffin, Philip F. Giampietro Tags: CLINICAL REPORT Source Type: research

New intragenic rearrangements in non ‐Finnish mulibrey nanism
We report here three patients in two distinct non‐Finnish families from North France who were first suspected to have Silver–Russell syndrome which failed to be confirmed on molecular analyses. Clinical features in the three patients led us to also consider the diagnosis of MULIBREY nanism. Sequencing of the TRIM37 gene showed the three patients shared a novel nonsense mutation (c.181 C>T p.Arg61*) in a heterozygous state. Quantitative fluorescent multiplex PCR identified a new deletion of exons 15 and 16 in TRIM37 in one isolated patient and another deletion of exon 9 in two siblings. Breakpoints of both the de...
Source: American Journal of Medical Genetics Part A - August 17, 2017 Category: Genetics & Stem Cells Authors: Florence Jobic, Gilles Morin, Catherine Vincent ‐Delorme, Estelle Cadet, Rosalie Cabry, Michèle Mathieu‐Dramard, Henri Copin, Jacques Rochette, Guillaume Jedraszak Tags: CLINICAL REPORT Source Type: research

Cystic kidneys in fetal Walker –Warburg syndrome with POMT2 mutation: Intrafamilial phenotypic variability in four siblings and review of literature
In conclusion, the heterogeneous clinical presentation in the four affected conceptions with POMT2 mutation expands the current clinical spectrum of POMT2‐associated WWS to include large cystic kidneys; and confirms intra‐familial variability in terms of brain, kidney, and eye anomalies. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - August 17, 2017 Category: Genetics & Stem Cells Authors: Marwa M. Nabhan, Nour ElKhateeb, Daniela A. Braun, Sungho Eun, Sahar N. Saleem, Heon YungGee, Friedhelm Hildebrandt, Neveen A. Soliman Tags: ORIGINAL ARTICLE Source Type: research

A splice ‐site variant in ANKRD11 associated with classical KBG syndrome
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - August 17, 2017 Category: Genetics & Stem Cells Authors: Karen J. Low, Alison Hills, Maggie Williams, Celia Duff ‐Farrier, Shane McKee, Sarah F. Smithson Tags: RESEARCH LETTER Source Type: research

Challenges of developing and conducting clinical trials in rare disorders
American Journal of Medical Genetics Part A,Volume 176, Issue 4, Page 773-783, April 2018. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - August 16, 2017 Category: Genetics & Stem Cells 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 - August 16, 2017 Category: Genetics & Stem Cells Source Type: research

Paternal transmission of a FMR1 full mutation allele
We present a 16‐year‐old girl with a mild fragile X syndrome phenotype. FMR1 gene study showed that the patient inherited a mosaic premutation‐full mutation with an unmethylated uninterrupted allele (175,>200 CGG) from her father. The father showed an 88 CGG uninterrupted unmethylated allele in blood and sperm cells. To our knowledge, this is the first case of a FMR1 mosaic premutation‐full mutation allele inherited from a PM father. In our opinion, the most likely explanation could be a postzygotic somatic expansion. We can conclude that in rare cases of a child with a full mutation whose mother does not carry ...
Source: American Journal of Medical Genetics Part A - August 16, 2017 Category: Genetics & Stem Cells Authors: Maria Isabel Alvarez ‐Mora, Miriam Guitart, Laia Rodriguez‐Revenga, Irene Madrigal, Elisabeth Gabau, Montserrat Milà Tags: CLINICAL REPORT Source Type: research

Epilepsy in fragile ‐X‐syndrome mimicking panayiotopoulos syndrome: Description of three patients
We describe the clinical features, EEG findings and evolution in three patients affected by Fragile‐X‐syndrome and epilepsy mimicking Panayiotopoulos syndrome. Age at seizure onset was between 4 and about 7 years. Seizures pattern comprised a constellation of autonomic symptoms with unilateral deviation of the eyes and ictal syncope. Duration of the seizures could be brief or lengthy. Interictal EEGs revealed functional multifocal abnormalities. The evolution was benign in all patients with seizures remission before the age of 14. This observation expands the spectrum of benign epileptic phenotypes present in Fragile...
Source: American Journal of Medical Genetics Part A - August 16, 2017 Category: Genetics & Stem Cells Authors: Paolo Bonanni, Susanna Casellato, Franco Fabbro, Susanna Negrin Tags: CLINICAL REPORT Source Type: research

Interstitial deletion 5p14.1 ‐p15.2 and 5q14.3‐q23.2 in a patient with clubfoot, blepharophimosis, arthrogryposis, and multiple congenital abnormalities
Interstitial deletions of the short and long arms of chromosome 5 are rare cytogenetic abnormalities. The 5p distal deletion is a genetic disorder characterized by a high‐pitched cat‐like cry, microcephaly, epicanthal folds, micrognathia, severe intellectual disability and motor delays. Previously, more than 46 patients with the 5q deletion have been reported. Here, we report de novo interstitial deletions involving 5p14.1–p15.2 and 5q14.3–q23.2 in a patient with multiple congenital abnormalities, including blepharophimosis, arthrogryposis, short neck, round face, pelvic kidney, agenesis of the corpus callo...
Source: American Journal of Medical Genetics Part A - August 16, 2017 Category: Genetics & Stem Cells Authors: Burhan Balta, Murat Erdogan, Ayse B. Ergul, Yavuz Sahin, Alper Ozcan Tags: CLINICAL REPORT Source Type: research

Clinical and molecular characterization of de novo loss of function variants in HNRNPU
DNA alterations in the 1q43‐q44 region are associated with syndromic neurodevelopmental disorders characterized by global developmental delay, intellectual disability, dysmorphic features, microcephaly, seizures, and agenesis of the corpus callosum. HNRNPU is located within the 1q43‐q44 region and mutations in the gene have been reported in patients with early infantile epileptic encephalopathy. Here, we report on the clinical presentation of four patients with de novo heterozygous HNRNPU loss‐of‐function mutations detected by clinical whole exome sequencing: c.651_660del (p.Gly218Alafs*118), c.1089G>A (p.Trp363...
Source: American Journal of Medical Genetics Part A - August 16, 2017 Category: Genetics & Stem Cells Authors: Magalie S. Leduc, Hsiao ‐Tuan Chao, Chunjing Qu, Magdalena Walkiewicz, Rui Xiao, Pilar Magoulas, Shujuan Pan, Joke Beuten, Weimin He, Jonathan A. Bernstein, Christian P. Schaaf, Fernando Scaglia, Christine M. Eng, Yaping Yang Tags: ORIGINAL ARTICLE Source Type: research

Prevalence of gastrointestinal symptoms in Angelman syndrome
Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, expressive speech impairment, movement disorder, epilepsy, and a happy demeanor. Children with AS are frequently reported to be poor feeders during infancy and as having gastrointestinal issues such as constipation, reflux, and abnormal food related behaviors throughout their lifetime. To assess the prevalence of gastrointestinal disorders in individuals with AS, we retrospectively analyzed medical records of 120 individuals seen at the Angelman Syndrome Clinic at Massachusetts General Hospital and 43 individuals seen at the Univers...
Source: American Journal of Medical Genetics Part A - August 16, 2017 Category: Genetics & Stem Cells Authors: Laura W. Glassman, Olivia R. Grocott, Portia A. Kunz, Anna M. Larson, Garret Zella, Kriston Ganguli, Ronald L. Thibert Tags: ORIGINAL ARTICLE Source Type: research

A novel heterozygous mutation in FGFR2 gene causing Pfeiffer syndrome
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - August 16, 2017 Category: Genetics & Stem Cells Authors: Renato A. Machado, Shirlene B. Ferreira, Luciane Martins, Mariana M. Ribeiro, Daniella R. B. Martelli, Ricardo D. Coletta, Marcos J. B. Aguiar, Herc ílio Martelli‐Júnior Tags: RESEARCH LETTER Source Type: research

Preaxial polydactyly in an individual with Wiedemann ‐Steiner syndrome caused by a novel nonsense mutation in KMT2A
Wiedemann‐Steiner syndrome (WDSTS) is an autosomal dominant disorder characterized by hypertrichosis, intellectual disability, and dysmorphic facial appearances (down‐slanted vertically narrow palpebral fissures, wide nasal bridge, broad nasal tip, and thick eyebrows). In 2012, Jones and co‐workers identified heterozygous mutations in KMT2A (lysine methyltransferase 2A) as the molecular cause of WDSTS. Although the phenotype of this syndrome continues to expand, the associated features are not fully understood. Here, we report WDSTS in a 12‐year‐old Japanese boy with a novel nonsense mutation in KMT2A. He had rig...
Source: American Journal of Medical Genetics Part A - August 16, 2017 Category: Genetics & Stem Cells Authors: Takashi Enokizono, Tatsuyuki Ohto, Ryuta Tanaka, Mai Tanaka, Hisato Suzuki, Aiko Sakai, Kazuo Imagawa, Hiroko Fukushima, Atsushi Iwabuti, Takashi Fukushima, Ryo Sumazaki, Tomoko Uehara, Toshiki Takenouchi, Kenjiro Kosaki Tags: CLINICAL REPORT Source Type: research

Estimation of live birth and population prevalence of Down syndrome in nine U.S. states
For all of the U.S. states with sufficient data, we estimated live birth and population prevalences for Down syndrome (DS). As social service resources vary between states, such data are important for public policy discussions and state planning. We predicted the actual and nonselective live birth prevalence, and population prevalence, for DS in nine U.S. states based on publicly available datasets from the Centers for Disease Control and Prevention and the Integrated Public Use Microdata Series. As of 2010, we estimated a population size for people with DS of 4,554 in MA (population prevalence 1 in 1,440), 6,101 in...
Source: American Journal of Medical Genetics Part A - August 16, 2017 Category: Genetics & Stem Cells Authors: Gert de Graaf, Frank Buckley, Jennifer Dever, Brian G. Skotko Tags: ORIGINAL ARTICLE Source Type: research

Progressive macrothrombocytopenia and hearing loss in a large family with DIAPH1 related disease
In this study, we describe a Japanese family with progressive hearing loss and macrothrombocytopenia. Using next‐generation and Sanger sequencing analyses, we identified a heterozygous variant in exon 27 of the DIAPH1 gene (NM_005219), c.3637C>T, p.R1213X. All patients in the family had sensorineural hearing loss and macrothrombocytopenia. None of the patients exhibited a tendency to bleed. No pathogenic variants were found in the MYH9 gene. Hearing loss began with high‐frequency loss during early childhood and progressed to severe hearing loss involving all frequencies. Analyses of the mean platelet volume and plat...
Source: American Journal of Medical Genetics Part A - August 16, 2017 Category: Genetics & Stem Cells Authors: Akira Ganaha, Tadashi Kaname, Ayano Shinjou, Yasutsugu Chinen, Kumiko Yanagi, Teruyuki Higa, Shunsuke Kondo, Mikio Suzuki Tags: CLINICAL REPORT Source Type: research

Challenges of developing and conducting clinical trials in rare disorders
Rare disease drug development is a rapidly expanding field. Clinical researchers in rare diseases face many challenges when conducting trials in small populations. Disease natural history is often poorly understood and the ability to detect clinically meaningful outcomes requires understanding of their rate of occurrence and variability, both of which contribute to difficulties in powering a study. Standard trial designs are not optimized to obtain adequate safety and efficacy data from small numbers of patients, so alternative designs (enrichment, crossover, adaptive, N‐of 1) need to be considered. The affected patients...
Source: American Journal of Medical Genetics Part A - August 16, 2017 Category: Genetics & Stem Cells Authors: Lucas Kempf, Jonathan C. Goldsmith, Robert Temple Tags: RESEARCH REVIEW Source Type: research

Continuous hypomethylation of the KCNQ1OT1:TSS ‐DMR in monochorionic twins discordant for Beckwith‐Wiedemann syndrome
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - August 16, 2017 Category: Genetics & Stem Cells Authors: Takanobu Inoue, Akie Nakamura, Keiko Matsubara, Hiromi Nyuzuki, Keisuke Nagasaki, Akira Oka, Maki Fukami, Masayo Kagami Tags: RESEARCH LETTER Source Type: research

The pregnancy in neurofibromatosis 1: A retrospective register ‐based total population study
The objective of this retrospective total population study was to form a view of the pregnancies of the patients with neurofibromatosis type 1 (NF1). A cohort of 1,410 Finnish patients with NF1 was acquired by searching NF1‐related inpatient and outpatient hospital visits and confirming the diagnoses by reviewing the medical records. Ten matched control persons per patient with NF1 were collected from Population Register Centre. Study persons were linked to data from Medical Birth Register and Care Register for Health Care through the personal identity code. Cesarean deliveries, hypertension/preeclampsia, and placental a...
Source: American Journal of Medical Genetics Part A - August 16, 2017 Category: Genetics & Stem Cells Authors: Jussi Lepp ävirta, Roope A. Kallionpää, Elina Uusitalo, Tero Vahlberg, Minna Pöyhönen, Susanna Timonen, Juha Peltonen, Sirkku Peltonen Tags: ORIGINAL ARTICLE Source Type: research

ALG13 ‐CDG in a male with seizures, normal cognitive development, and normal transferrin isoelectric focusing
ALG13‐CDG has been recently discovered as a disorder of severe developmental, intellectual and speech disability, microcephaly, visual abnormalities, seizures, hepatomegaly, coagulation abnormalities, and abnormal serumtransferrin isoelectric focusing in serum. A male with seizures, delayed motor, and speech development, but normal cognition carried a hemizygous, predicted pathogenic ALG13 variant (p.E463G). N‐glycosylation studies in plasma were normal. ICAM‐1 expression was decreased in patient fibroblasts, supporting the variant's pathogenicity. Adding D‐galactose to the patient's fibroblast culture increased IC...
Source: American Journal of Medical Genetics Part A - August 4, 2017 Category: Genetics & Stem Cells Authors: Therese E. Gadomski, Melody Bolton, Majid Alfadhel, Chris Dvorak, Olalekan A. Ogunsakin, Stephen L. Nelson, Eva Morava Tags: CLINICAL REPORT Source Type: research

A novel genetic syndrome with STARD9 mutation and abnormal spindle morphology
Intellectual disability (ID) is one of neurodevelopmental disorders characterized by serious defects in both intelligence and adaptive behavior. Although it has been suggested that genetic aberrations associated with the process of cell division underlie ID, the cytological evidence for mitotic defects in actual patient's cells is rarely reported. Here, we report a novel mutation in the STARD9 (also known as KIF16A) gene found in a patient with severe ID, characteristic features, epilepsy, acquired microcephaly, and blindness. Using whole‐exome sequence analysis, we sequenced potential candidate genes in the patient. We ...
Source: American Journal of Medical Genetics Part A - August 4, 2017 Category: Genetics & Stem Cells Authors: Nobuhiko Okamoto, Yuki Tsuchiya, Fuyuki Miya, Tatsuhiko Tsunoda, Kumiko Yamashita, Keith A. Boroevich, Mitsuhiro Kato, Shinji Saitoh, Mami Yamasaki, Yonehiro Kanemura, Kenjiro Kosaki, Daiju Kitagawa Tags: ORIGINAL ARTICLE Source Type: research

A human case of SLC35A3 ‐related skeletal dysplasia
Researchers have identified a subset of Holstein having a range of skeletal deformities, including vertebral anomalies, referred to as complex vertebral malformation due to mutations in the SLC35A3 gene. Here, we report the first case in humans of SLC35A3‐related vertebral anomalies. Our patient had prenatally diagnosed anomalous vertebrae, including butterfly, and hemivertebrae throughout the spine, as well as cleft palate, micrognathia, patent foramen ovale, patent ductus arteriosus, posterior embryotoxon, short limbs, camptodactyly, talipes valgus, rocker bottom feet, and facial dysmorphism including proptosis, nevus ...
Source: American Journal of Medical Genetics Part A - August 4, 2017 Category: Genetics & Stem Cells Authors: Andrew C. Edmondson, Emma C. Bedoukian, Matthew A. Deardorff, Donna M. McDonald ‐McGinn, Xueli Li, Miao He, Elaine H. Zackai Tags: CLINICAL REPORT Source Type: research

Skewed X ‐inactivation in a family with DLG3‐associated X‐linked intellectual disability
We report on an XLID family with a novel DLG3 mutation. The 12‐year‐old male index patient had moderate intellectual disability (ID) and dysmorphic features. The mutation was also present in four female relatives. A maternal aunt had moderate ID and significantly skewed X‐inactivation favorably inactivating the normal DLG3 allele. The proband's healthy mother also had skewed X‐inactivation but in the opposite direction (i.e., inactivation of the mutated allele). Two other female relatives had intermediate cognitive phenotypes and random X‐inactivation. This family broadens the mutational and phenotypical spectrum...
Source: American Journal of Medical Genetics Part A - August 4, 2017 Category: Genetics & Stem Cells Authors: Laura Gieldon, Luisa Mackenroth, Elitza Betcheva ‐Krajcir, Andreas Rump, Stefanie Beck‐Wödl, Jens Schallner, Nataliya Di Donato, Evelin Schröck, Andreas Tzschach Tags: CLINICAL REPORT Source Type: research

Two unrelated children with overlapping 6q25.3 deletions, motor speech disorders, and language delays
We report on a case (Patient 1, age 7 years) with a de novo 6q25.3‐qter deletion, 11.1 Mb long and encompassing 108 genes, and a case (Patient 2, age 5 years) with an inherited interstitial 6q25.3 deletion, located within Patient 1's deletion region and 403 kb long, the smallest 6q25 deletion reported to date. Both children have hypotonia, motor speech disorders, and expressive language delays. Patient 1's speech was characterized by childhood apraxia of speech (CAS) and dysarthria. Other findings include developmental delay, ataxic cerebral palsy, optic nerve dysplagia, and atypical brain morphologies rega...
Source: American Journal of Medical Genetics Part A - August 2, 2017 Category: Genetics & Stem Cells Authors: Beate Peter, Hope Lancaster, Caitlin Vose, Amna Fares, Isabelle Schrauwen, Matthew Huentelman Tags: ORIGINAL ARTICLE Source Type: research

Neonatal fractures as a presenting feature of LMOD3 ‐associated congenital myopathy
Nemaline myopathy is a rare inherited disorder characterized by weakness, hypotonia, and depressed deep tendon reflexes. It is clinically and genetically heterogeneous, with the most severe phenotype presenting as perinatal akinesia, severe muscle weakness, feeding difficulties and respiratory failure, leading to early mortality. Pathogenic variants in 12 genes, encoding components of the sarcomere or factors related to myogenesis, have been reported in patients affected with the disorder. Here, we describe an early, lethal presentation of decreased fetal movements, hypotonia, muscle weakness, and neonatal respiratory fail...
Source: American Journal of Medical Genetics Part A - August 1, 2017 Category: Genetics & Stem Cells Authors: Megan Abbott, Mahim Jain, Rachel Pferdehirt, Yuqing Chen, Alyssa Tran, Mehmet B. Duz, Mehmet Seven, Richard A. Gibbs, Donna Muzny, Brendan Lee, Ronit Marom, Lindsay C. Burrage Tags: CLINICAL REPORT Source Type: research

Vitamin D levels in Smith ‐Lemli‐Opitz syndrome
Smith–Lemli–Opitz syndrome (SLOS) is an autosomal recessive congenital malformation syndrome caused by mutations in the 7‐dehydrocholesterol reductase gene. This inborn error of cholesterol synthesis leads to elevated concentrations of 7‐dehydrocholesterol (7‐DHC). 7‐DHC also serves as the precursor for vitamin D synthesis. Limited data is available on vitamin D levels in individuals with SLOS. Due to elevated concentrations of 7‐DHC, we hypothesized that vitamin D status would be abnormal and possibly reach toxic levels in patients with SLOS. Through a retrospective analysis of medical records betwee...
Source: American Journal of Medical Genetics Part A - August 1, 2017 Category: Genetics & Stem Cells Authors: Miyad Movassaghi, Simona Bianconi, Richard Feinn, Christopher A. Wassif, Forbes D. Porter Tags: ORIGINAL ARTICLE Source Type: research

Co ‐occurrence of Sturge–Weber syndrome and Klippel–Trenaunay–Weber syndrome phenotype: Consideration of the historical aspect
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - August 1, 2017 Category: Genetics & Stem Cells Authors: Yuri Sakaguchi, Toshiki Takenouchi, Tomoko Uehara, Kazuo Kishi, Takao Takahashi, Kenjiro Kosaki Tags: RESEARCH LETTER Source Type: research

Identification of STAC3 variants in non ‐Native American families with overlapping features of Carey–Fineman–Ziter syndrome and Moebius syndrome
Horstick et al. (2013) previously reported a homozygous p.Trp284Ser variant in STAC3 as the cause of Native American myopathy (NAM) in 5 Lumbee Native American families with congenital hypotonia and weakness, cleft palate, short stature, ptosis, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH). Here we present two non‐Native American families, who were found to have STAC3 pathogenic variants. The first proband and her affected older sister are from a consanguineous Qatari family with a suspected clinical diagnosis of Carey–Fineman–Ziter syndrome (CFZS) based on features o...
Source: American Journal of Medical Genetics Part A - August 1, 2017 Category: Genetics & Stem Cells Authors: Aida Telegrafi, Bryn D. Webb, Sarah M. Robbins, Carlos E. Speck ‐Martins, David FitzPatrick, Leah Fleming, Richard Redett, Andreas Dufke, Gunnar Houge, Jeske J. T. van Harssel, Alain Verloes, Angela Robles, Irini Manoli, Elizabeth C. Engle, , Ethylin W. Tags: CLINICAL REPORT Source Type: research

Expanding the phenotype of DST ‐related disorder: A case report suggesting a genotype/phenotype correlation
The gene DST encodes for the large protein BPAG1 involved in hemidesmosomes. Its alternative splicing gives rise to tissue‐enriched isoforms in brain, muscle, and skin. The few patients described so far with bi‐allelic mutations in the DST gene have either a skin phenotype of epidermolysis bullosa simplex or a neurological phenotype. Here, we report a 17‐year‐old female individual presenting with a more complex phenotype consisting of both skin and neuronal involvement, in addition to several previously unreported findings, such as iris heterochromia, cataract, hearing impairment, syringomyelia, behavioral, and gas...
Source: American Journal of Medical Genetics Part A - August 1, 2017 Category: Genetics & Stem Cells Authors: Gerarda Cappuccio, Michele Pinelli, Annalaura Torella, Marianna Alagia, Renata Auricchio, Annamaria Staiano, Vincenzo Nigro, , Nicola Brunetti ‐Pierri Tags: CLINICAL REPORT Source Type: research

Three cases of multi ‐generational Pompe disease: Are current practices missing diagnostic and treatment opportunities?
In this report, we describe three families with multiple individuals in multiple generations affected by both infantile and late‐onset clinical presentations of Pompe disease. The presence of multi‐generational disease within these families highlights the importance of subsequent risk assessment through medical history and physical examination, with a low threshold for the screening of a proband's family members. We recommend enzymology (GAA activity assay) as the first screening method, as opposed to targeted mutation analysis, for at‐risk family members. Given that the initial symptoms of the slowly progressive lat...
Source: American Journal of Medical Genetics Part A - August 1, 2017 Category: Genetics & Stem Cells Authors: Paul McIntosh, Stephanie Austin, Jennifer Sullivan, Lauren Bailey, Carrie Bailey, David Viskochil, Priya S. Kishnani Tags: ORIGINAL ARTICLE Source Type: research

Best practices in peri ‐operative management of patients with skeletal dysplasias
Patients with skeletal dysplasia frequently require surgery. This patient population has an increased risk for peri‐operative complications related to the anatomy of their upper airway, abnormalities of tracheal‐bronchial morphology and function; deformity of their chest wall; abnormal mobility of their upper cervical spine; and associated issues with general health and body habitus. Utilizing evidence analysis and expert opinion, this study aims to describe best practices regarding the peri‐operative management of patients with skeletal dysplasia. A panel of 13 multidisciplinary international experts participated in...
Source: American Journal of Medical Genetics Part A - August 1, 2017 Category: Genetics & Stem Cells Authors: Klane K. White, Viviana Bompadre, Michael J. Goldberg, Michael B. Bober, Tae ‐Joon Cho, Julie E. Hoover‐Fong, Melita Irving, William G. Mackenzie, Shawn E. Kamps, Cathleen Raggio, Gregory J. Redding, Samantha S. Spencer, Ravi Savarirayan, Mary C. Ther Tags: ORIGINAL ARTICLE Source Type: research

Monoallelic FGFR3 and Biallelic ALPL mutations in a Thai girl with hypochondroplasia and hypophosphatasia
In conclusion, we describe a unique case with monoallelic FGFR3 and biallelic ALPL mutations leading to features of both hypochondroplasia and hypophosphatasia. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - August 1, 2017 Category: Genetics & Stem Cells Authors: Thantrira Porntaveetus, Chalurmpon Srichomthong, Kanya Suphapeetiporn, Vorasuk Shotelersuk Tags: CLINICAL REPORT Source Type: research

Co ‐occurring Down syndrome and SUCLA2‐related mitochondrial depletion syndrome
We describe two siblings of Hispanic descent with SUCLA2‐related mitochondrial depletion syndrome (encephalomyopathic form with methylmalonic aciduria); the older sibling is additionally affected with trisomy 21. SUCLA2 sequencing identified homozygous p.Arg284Cys pathogenic variants in both patients. This mutation has previously been identified in four individuals of Italian and Caucasian descent. The older sibling with concomitant disease has a more severe phenotype than what is typically described in patients with either SUCLA2‐related mitochondrial depletion syndrome or Down syndrome alone. The younger sibling, who...
Source: American Journal of Medical Genetics Part A - July 27, 2017 Category: Genetics & Stem Cells Authors: Natario L. Couser, Daniel S. Marchuk, Laurie D. Smith, Alexandra Arreola, Kathleen A. Kaiser ‐Rogers, Joseph Muenzer, Arti Pandya, Muge Gucsavas‐Calikoglu, Cynthia M. Powell Tags: CLINICAL REPORT Source Type: research

Autopsy findings in EPG5 ‐related Vici syndrome with antenatal onset
Vici syndrome is one of the most extensive inherited human multisystem disorders and due to recessive mutations in EPG5 encoding a key autophagy regulator with a crucial role in autophagosome–lysosome fusion. The condition presents usually early in life, with features of severe global developmental delay, profound failure to thrive, (acquired) microcephaly, callosal agenesis, cataracts, cardiomyopathy, hypopigmentation, and combined immunodeficiency. Clinical course is variable but usually progressive and associated with high mortality. Here, we present a fetus, offspring of consanguineous parents, in whom callosal a...
Source: American Journal of Medical Genetics Part A - July 27, 2017 Category: Genetics & Stem Cells Authors: Renaud Touraine, Annie Laquerri ère, Carmen‐Adina Petcu, Florent Marguet, Susan Byrne, Rachael Mein, Shu Yau, Shehla Mohammed, Laurent Guibaud, Mathias Gautel, Heinz Jungbluth Tags: CLINICAL REPORT Source Type: research

Noonan syndrome in diverse populations
In this study, individuals from diverse populations with NS were evaluated clinically and by facial analysis technology. Clinical data and images from 125 individuals with NS were obtained from 20 countries with an average age of 8 years and female composition of 46%. Individuals were grouped into categories of African descent (African), Asian, Latin American, and additional/other. Across these different population groups, NS was phenotypically similar with only 2 of 21 clinical elements showing a statistically significant difference. The most common clinical characteristics found in all population groups included widely s...
Source: American Journal of Medical Genetics Part A - July 27, 2017 Category: Genetics & Stem Cells Authors: Paul Kruszka, Antonio R. Porras, Yonit A. Addissie, Ang élica Moresco, Sofia Medrano, Gary T. K. Mok, Gordon K. C. Leung, Cedrik Tekendo‐Ngongang, Annette Uwineza, Meow‐Keong Thong, Premala Muthukumarasamy, Engela Honey, Ekanem N. Ekure, Ogochukwu J. Tags: ORIGINAL ARTICLE Source Type: research

Biallelic COL3A1 mutations result in a clinical spectrum of specific structural brain anomalies and connective tissue abnormalities
Vascular Ehlers–Danlos syndrome (type IV) is an autosomal dominant disorder caused by heterozygous variants of COL3A1. We identified biallelic COL3A1 variants in two unrelated families. In a 3‐year‐old female with developmental delay the nonsense variant c.1282C>T, p.(Arg428*) was detected in combination the c.2057delC, p.(Pro686Leufs*105) frame shift variant. Both compound heterozygous variants were novel. This patient was born with bilateral clubfoot, joint laxity, and dysmorphic facial features. At the age of 2 years she developed an aneurysmal brain hemorrhage. Cerebral MRI showed a peculiar pattern of pro...
Source: American Journal of Medical Genetics Part A - July 25, 2017 Category: Genetics & Stem Cells Authors: Denise Horn, Eberhard Siebert, Ulrich Seidel, Imma Rost, Karin Mayer, Rami Abou Jamra, Diana Mitter, Uwe Kornak Tags: CLINICAL REPORT Source Type: research

Congenital disorders of glycosylation: The Saudi experience
We retrospectively reviewed Saudi patients who had a congenital disorder of glycosylation (CDG). Twenty‐seven Saudi patients (14 males, 13 females) from 13 unrelated families were identified. Based on molecular studies, the 27 CDG patients were classified into different subtypes: ALG9‐CDG (8 patients, 29.5%), ALG3‐CDG (7 patients, 26%), COG6‐CDG (7 patients, 26%), MGAT2‐CDG (3 patients, 11%), SLC35A2‐CDG (1 patient), and PMM2‐CDG (1 patient). All the patients had homozygous gene mutations. The combined carrier frequency of CDG for the encountered founder mutations in the Saudi population is 11.5 per 10,000, w...
Source: American Journal of Medical Genetics Part A - July 25, 2017 Category: Genetics & Stem Cells Authors: Sarah Alsubhi, Amal Alhashem, Eissa Faqeih, Majid Alfadhel, Abdullah Alfaifi, Waleed Altuwaijri, Saud Alsahli, Hesham Aldhalaan, Fowzan S. Alkuraya, Khalid Hundallah, Adel Mahmoud, Ali Alasmari, Fuad Al Mutairi, Hanem Abduraouf, Layan AlRasheed, Saad Alsh Tags: ORIGINAL ARTICLE Source Type: research

Variable expressivity and incomplete penetrance in a large family with non ‐classical Diamond‐Blackfan anemia associated with ribosomal protein L11 splicing variant
This report summarizes the prevalence of non‐anemia findings in DBA7 and describes a non‐classical familial presentation of DBA7 more associated with thumb anomalies than with anemia. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - July 25, 2017 Category: Genetics & Stem Cells Authors: Colleen M. Carlston, Zeinab A. Afify, Janice C. Palumbos, Heidi Bagley, Carlos Barbagelata, Whitney L. Wooderchak ‐Donahue, Rong Mao, John C. Carey Tags: ORIGINAL ARTICLE Source Type: research

Additional report on Moreno ‐Nishimura‐Schmidt overgrowth syndrome
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - July 25, 2017 Category: Genetics & Stem Cells Authors: Atsuhiko Handa, Koji Muroya, Tomohiro Ishii, Gen Nishimura Tags: RESEARCH LETTER Source Type: research

Novel PRPS1 gain ‐of‐function mutation in a patient with congenital hyperuricemia and facial anomalies
We report on a 7‐year‐old boy with congenital hyperuricemia, urolithiasis, developmental delay, short stature, hypospadias, and facial dysmorphisms. His mother also suffered from hyperuricemia that was diagnosed at age 13 years. A novel PRPS1 missense mutation (c.573G>C, p.[Leu191Phe]) was detected in the proband and his mother. Enzyme activity analysis confirmed superactivity of PRPP synthetase. Analysis of the crystal structure of human PRPPS suggests that the Leu191Phe mutation affects the architecture of both allosteric sites, thereby preventing the allosteric inhibition of the enzyme. The family reported here b...
Source: American Journal of Medical Genetics Part A - July 25, 2017 Category: Genetics & Stem Cells Authors: Joseph Porrmann, Elitza Betcheva ‐Krajcir, Nataliya Di Donato, Anne‐Karin Kahlert, Jens Schallner, Andreas Rump, Evelin Schröck, Doreen Dobritzsch, Jeroen Roelofsen, André B. P. van Kuilenburg, Andreas Tzschach Tags: CLINICAL REPORT Source Type: research

Agenesis of the corpus callosum, developmental delay, autism spectrum disorder, facial dysmorphism, and posterior polymorphous corneal dystrophy associated with ZEB1 gene deletion
We report on a girl diagnosed prenatally with agenesis of the corpus callosum (ACC) on fetal ultrasound and MRI. On postnatal follow‐up she was noted to have developmental delay, facial dysmorphism, autism spectrum disorder, and posterior polymorphous corneal dystrophy (PPD). Array‐comparative genomic hybridization analysis (Array‐CGH) showed a 2.05 Mb de novo interstitial deletion at 10p11.23p11.22. The deleted region overlaps 1 OMIM Morbid Map gene, ZEB1 (the zinc finger E‐box binding homeobox transcription factor 1), previously associated with posterior polymorphous corneal dystrophy type 3 (PPCD3). To ou...
Source: American Journal of Medical Genetics Part A - July 25, 2017 Category: Genetics & Stem Cells Authors: Ayeshah Chaudhry, Brian H. Chung, Dimitri J. Stavropoulos, Marcela P. Araya, Asim Ali, Elise Heon, David Chitayat Tags: CLINICAL REPORT Source Type: research

Whole exome sequencing identified genetic variations in Chinese hemangioblastoma patients
Hemangioblastomas (HBs) are uncommon tumors characterized by the presence of inactivating alterations in the von Hippel‐Lindau (VHL) gene in inherited cases and by infrequent somatic mutation in sporadic entities. We performed whole exome sequencing on 11 HB patients to further elucidate the genetics of HBs. A total of 270 somatic variations in 219 genes, of which there were 86 mutations in 67 genes, were found in sporadic HBs, and 184 mutations were found in 154 genes in familial HBs. C: G>T: A and T: A>C: G mutations are relatively common in most HB patients. Genes harboring the most significant mutations include...
Source: American Journal of Medical Genetics Part A - July 25, 2017 Category: Genetics & Stem Cells Authors: Dexuan Ma, Jingyun Yang, Ying Wang, Xiang Huang, Guhong Du, Liangfu Zhou Tags: ORIGINAL ARTICLE Source Type: research

MED resulting from recessively inherited mutations in the gene encoding calcium ‐activated nucleotidase CANT1
Multiple Epiphyseal Dysplasia (MED) is a relatively mild skeletal dysplasia characterized by mild short stature, joint pain, and early‐onset osteoarthropathy. Dominantly inherited mutations in COMP, MATN3, COL9A1, COL9A2, and COL9A3, and recessively inherited mutations in SLC26A2, account for the molecular basis of disease in about 80–85% of the cases. In two families with recurrent MED of an unknown molecular basis, we used exome sequencing and candidate gene analysis to identify homozygosity for recessively inherited missense mutations in CANT1, which encodes calcium‐activated nucleotidase 1. The MED phenotype ...
Source: American Journal of Medical Genetics Part A - July 25, 2017 Category: Genetics & Stem Cells Authors: Karthika Balasubramanian, Bing Li, Deborah Krakow, Lisette Nevarez, Patric J. Ho, Julia A. Ainsworth, Deborah A. Nickerson, Michael J. Bamshad, LaDonna Immken, Ralph S. Lachman, Daniel H. Cohn Tags: ORIGINAL ARTICLE Source Type: research