Experiences in feeding and gastrointestinal dysfunction in children with CHARGE syndrome
Feeding issues are very common in individuals with CHARGE syndrome and can lead to increased morbidity and mortality. The aim of this study was to expand upon the limited knowledge base of feeding and gastrointestinal issues in individuals with CHARGE syndrome. Parents of individuals (age range 1–18 years) with CHARGE syndrome, with or without feeding/gastrointestinal issues, were recruited through international CHARGE syndrome associations and CHARGE syndrome Facebook pages. Parents completed three questionnaires: CHARGE diagnostic characteristics; Pediatric Assessment Scale for Severe Feeding Problems © and Pe...
Source: American Journal of Medical Genetics Part A - September 22, 2017 Category: Genetics & Stem Cells Authors: Meghan Macdonald, Alexandra Hudson, Angela Bladon, Elyanne Ratcliffe, Kim Blake Tags: ORIGINAL ARTICLE Source Type: research

The 22q11.2 deletion syndrome: Cancer predisposition, platelet abnormalities and cytopenias
American Journal of Medical Genetics Part A, EarlyView. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 22, 2017 Category: Genetics & Stem Cells Authors: Michele P. Lambert , Abinaya Arulselvan , Amanda Schott , Stephen J. Markham , Terrance B. Crowley , Elaine H. Zackai , Donna M. McDonald ‐McGinn 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 - September 22, 2017 Category: Genetics & Stem Cells Source Type: research

Expected weight gain for children with microcephalic osteodysplastic primordial dwarfism type II
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 22, 2017 Category: Genetics & Stem Cells Authors: Angela L. Duker, Timothy Niiler, Michael B. Bober Tags: RESEARCH LETTER Source Type: research

Loss ‐of‐function variants in NFIA provide further support that NFIA is a critical gene in 1p32‐p31 deletion syndrome: A four patient series
The association between 1p32‐p31 contiguous gene deletions and a distinct phenotype that includes anomalies of the corpus callosum, ventriculomegaly, developmental delay, seizures, and dysmorphic features has been long recognized and described. Recently, the observation of overlapping phenotypes in patients with chromosome translocations that disrupt NFIA (Nuclear factor I/A), a gene within this deleted region, and NFIA intragenic deletions has led to the hypothesis that NFIA is a critical gene within this region. The wide application and increasing accessibility of whole exome sequencing (WES) has helped identify new ca...
Source: American Journal of Medical Genetics Part A - September 22, 2017 Category: Genetics & Stem Cells Authors: Anya Revah ‐Politi, Mythily Ganapathi, Louise Bier, Megan T. Cho, David B. Goldstein, Parisa Hemati, Alejandro Iglesias, Jane Juusola, John Pappas, Slavé Petrovski, Ashley L. Wilson, Vimla S. Aggarwal, Kwame Anyane‐Yeboa Tags: CLINICAL REPORT Source Type: research

From clinical observations and molecular dissection to novel therapeutic strategies for primary immunodeficiency disorders
The field of primary immunodeficiency diseases (PID) is rapidly expanding with more than 300 genetically defined disorders that have been clinically described and molecularly analyzed. The molecular dissection of these entities has led to the discovery of new immunologic pathways and to novel and effective disease‐specific therapies. This review provides a summary of these primary immune defects categorized by clinical phenotype and molecular similarity as defined by the International Union of Immunologic Societies (IUIS) Expert Committee for PID. In this synopsis, we discuss the molecular basis of various categories of ...
Source: American Journal of Medical Genetics Part A - September 21, 2017 Category: Genetics & Stem Cells Authors: Hans D. Ochs, Daniel Petroni Tags: RESEARCH REVIEW Source Type: research

From clinical observations and molecular dissection to novel therapeutic strategies for primary immunodeficiency disorders
American Journal of Medical Genetics Part A,Volume 176, Issue 4, Page 784-803, April 2018. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 21, 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 - September 21, 2017 Category: Genetics & Stem Cells Source Type: research

Corrigendum: Psychiatric and psychological aspects in the Ehlers –Danlos syndromes
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 21, 2017 Category: Genetics & Stem Cells Authors: Andrea Bulbena ‐Cabré, Antonio Bulbena Tags: CORRIGENDUM Source Type: research

Confirmation that RIPK4 mutations cause not only Bartsocas ‐Papas syndrome but also CHAND syndrome
We report here two cases of RIPK4 homozygous mutations in a fetus with severe Bartsocas‐Papas syndrome and a patient with CHAND syndrome. The patient with CHAND syndrome harbored the same mutation as the one identified in the family previously reported. We thus confirm the implication of RIPK4 gene in CHAND syndrome in addition to Bartsocas‐Papas syndrome and discuss genotype/phenotype correlations. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 21, 2017 Category: Genetics & Stem Cells Authors: Tiffany Busa, Mohammed Jeraiby, Alix Cl émenson, Sylvie Manouvrier, Viviana Granados, Nicole Philip, Renaud Touraine Tags: CLINICAL REPORT Source Type: research

A cohort study of multiple families with FBN1 p.R650C variant, ectopia lentis, and low but not absent risk for aortopathy
Marfan syndrome is a multisystem disease with cardiovascular, ophthalmologic, and skeletal features. Diagnosis is made clinically with emphasis on presence of aortic root dilation and ectopia lentis (EL). Most individuals meeting these criteria have a pathogenic variant in FBN1, usually unique or observed rarely. Individuals with EL alone may also have FBN1 pathogenic variants, and the risk for aortic disease is not well known. We identified a unique cohort of 31 individuals (mean age 29, range 2–78) from nine families ascertained by a proband with EL alone, who had the same FBN1 p.R650C variant. Comparison was made ...
Source: American Journal of Medical Genetics Part A - September 21, 2017 Category: Genetics & Stem Cells Authors: Lohith Vatti, Sara M. Fitzgerald ‐Butt, Kim L. McBride Tags: ORIGINAL ARTICLE Source Type: research

Women who carry a fragile X premutation are biologically older than noncarriers as measured by telomere length
Women who carry a fragile X premutation, defined as having 55–200 unmethylated CGG repeats in the 5′ UTR of the X‐linked FMR1 gene, have a 20‐fold increased risk for primary ovarian insufficiency (FXPOI). We tested the hypothesis that women with a premutation + FXPOI have shorter telomeres than those without FXPOI because they are “biologically older.” Using linear regression, we found that women carrying a premutation (n = 172) have shorter telomeres and hence, are “biologically older” than women carrying the normal size allele (n = 81). Str...
Source: American Journal of Medical Genetics Part A - September 21, 2017 Category: Genetics & Stem Cells Authors: Igor Albizua, Benjamin L. Rambo ‐Martin, Emily G. Allen, Weiya He, Ashima S. Amin, Stephanie L. Sherman Tags: ORIGINAL ARTICLE Source Type: research

The spectrum of DNMT3A variants in Tatton –Brown–Rahman syndrome overlaps with that in hematologic malignancies
De novo, germline variants in DNMT3A cause Tatton–Brown–Rahman syndrome (TBRS). This condition is characterized by overgrowth, distinctive facial appearance, and intellectual disability. Somatic DNMT3A variants frequently occur in hematologic malignances, particularly acute myeloid leukemia. The Arg882 residue is the most common site of somatic DNMT3A variants, and has also been altered in patients with TBRS. Here we present three additional patients with this disorder attributed to DNMT3A germline variants that disrupt the Arg882 codon, suggesting that this codon may be a germline mutation hotspot in this diso...
Source: American Journal of Medical Genetics Part A - September 21, 2017 Category: Genetics & Stem Cells Authors: Wei Shen, Jennifer M. Heeley, Colleen M. Carlston, Rocio Acuna ‐Hidalgo, Willy M. Nillesen, Karin M. Dent, Ganka V. Douglas, Kara L. Levine, Pinar Bayrak‐Toydemir, Carlo L. Marcelis, Marwan Shinawi, John C. Carey Tags: ORIGINAL ARTICLE Source Type: research

The Influence of trisomy 21 on facial form and variability
Triplication of chromosome 21 (trisomy 21) results in Down syndrome (DS), the most common live‐born human aneuploidy. Individuals with DS have a unique facial appearance that can include form changes and altered variability. Using 3D photogrammatic images, 3D coordinate locations of 20 anatomical landmarks, and Euclidean Distance Matrix Analysis methods, we quantitatively test the hypothesis that children with DS (n = 55) exhibit facial form and variance differences relative to two different age‐matched (4–12 years) control samples of euploid individuals: biological siblings of individuals with DS (...
Source: American Journal of Medical Genetics Part A - September 21, 2017 Category: Genetics & Stem Cells Authors: John M. Starbuck, Theodore M. Cole, Roger H. Reeves, Joan T. Richtsmeier 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 - September 18, 2017 Category: Genetics & Stem Cells Tags: the AJMG SEQUENCE: Decoding News and Trends for the Medical Genetics Community by Deborah Levenson Source Type: research

New intellectual disability syndrome identified
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 18, 2017 Category: Genetics & Stem Cells Tags: the AJMG SEQUENCE: Decoding News and Trends for the Medical Genetics Community by Deborah Levenson Source Type: research

Genome ‐wide cell free fetal DNA screening spots variations standard screening doesn't
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 18, 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 - September 18, 2017 Category: Genetics & Stem Cells Tags: ISSUE INFORMATION Source Type: research

Table of Contents, Volume 173A, Number 10, October 2017
(Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 18, 2017 Category: Genetics & Stem Cells Tags: ISSUE INFORMATION Source Type: research

Cover Image, Volume 173A, Number 10, October 2017
The cover image, by Rani A. Bashir et al., is based on the Original Article Lin‐Gettig syndrome: Craniosynostosis expands the spectrum of the KAT6B related disorders, DOI: 10.1002/ajmg.a.38355. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 18, 2017 Category: Genetics & Stem Cells Authors: Rani A. Bashir, Abhijit Dixit, Caitlin Goedhart, Jillian S. Parboosingh, Allan M. Innes, , Patrick Ferreira, Shabih U. Hasan, Ping ‐Yee B. Au Tags: COVER IMAGE Source Type: research

Compound heterozygous TRPV4 mutations in two siblings with a complex phenotype including severe intellectual disability and neuropathy
TRPV4 encodes a polymodal calcium‐permeable plasma membrane channel. Dominant pathogenic mutations in TRPV4 lead to a wide spectrum of abnormal phenotypes. This is the first report of biallelic TRPV4 mutations and we describe two compound heterozygous siblings presenting with a complex phenotype including severe neuromuscular involvement. In light of previously well described dominant inheritance for TRPV4‐related neuromuscular disease, our study suggests a role for compound heterozygosity and loss‐of‐function as a potential novel disease mechanism for this group of disorders. Profound intellectual disability was a...
Source: American Journal of Medical Genetics Part A - September 12, 2017 Category: Genetics & Stem Cells Authors: My Linh Thibodeau, Colin H. Peters, Katelin N. Townsend, Yaoqing Shen, Glenda Hendson, Shelin Adam, Kathryn Selby, Patrick M. Macleod, Cynthia Gershome, Peter Ruben, Steven J. M. Jones, , Jan M. Friedman, William T. Gibson, Gabriella A. Horvath Tags: CLINICAL REPORT Source Type: research

Treating pediatric neuromuscular disorders: The future is now
American Journal of Medical Genetics Part A,Volume 176, Issue 4, Page 804-841, April 2018. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 10, 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 - September 10, 2017 Category: Genetics & Stem Cells Source Type: research

Intrafamilial variability of the triphalangeal thumb phenotype in a Dutch population: Evidence for phenotypic progression over generations?
Triphalangeal thumbs (TPTs) are regularly caused by mutations in the ZRS in LMBR1. Phenotypic variability can be present in TPT‐families. However, recent observations suggest an increased occurrence of severe phenotypes in the Dutch TPT‐population. Therefore, the aim of this study is to investigate the progression of the clinical severity of TPT‐phenotype through generations. Index patients from a Dutch TPT‐population were identified. A 105C>G mutation in the ZRS has previously been confirmed in this population. Questionnaires regarding family occurrence and phenotypes were distributed. Subsequently, families we...
Source: American Journal of Medical Genetics Part A - September 10, 2017 Category: Genetics & Stem Cells Authors: Martijn Baas, Jacob W.P. Potuijt, Steven E.R. Hovius, A. Jeannette M. Hoogeboom, Robert ‐Jan H. Galjaard, Christianne A. van Nieuwenhoven Tags: ORIGINAL ARTICLE Source Type: research

Chimerism for 20q11.2 microdeletion of GDF5 explains discordant phenotypes in monochorionic ‐diamniotic twins
Microdeletions of 20q11.2 are rare but have been associated with characteristic clinical findings. A 1.6 Mb minimal critical region has been identified that includes three OMIM genes: GDF5, EPB41L1, and SAMHD. Here we describe a male monozygotic, monochorionic‐diamniotic twin pair with discordant phenotypes, one with multiple findings that overlap with those reported in 20q11.2 deletions, and the other unaffected. Microarray analysis revealed mosaicism for a 363 Kb deletion encompassing GDF5 in the peripheral blood of both twins, which was confirmed by FISH. Subsequent FISH on buccal cells identified the de...
Source: American Journal of Medical Genetics Part A - September 8, 2017 Category: Genetics & Stem Cells Authors: Matthew M. Meredith, Beau Crabb, Marcelo Vargas, Betsy A. Hirsch Tags: CLINICAL REPORT Source Type: research

Peeling skin syndrome associated with novel variant in FLG2 gene
We describe multiple family members from a consanguineous Saudi family with peeling skin syndrome. Next Generation Sequencing identifies a cosegregating novel variant in FLG2 c.632C>G (p.Ser211*) as a likely etiology in this family. Here, we reported on the clinical manifestation of homozygous loss of function variant in FLG2 as a disease‐causing gene for peeling skin syndrome and expand the dermatology findings. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 8, 2017 Category: Genetics & Stem Cells Authors: Ahmed Alfares, Sultan Al ‐Khenaizan, Fuad Al Mutairi Tags: CLINICAL REPORT Source Type: research

Variable phenotypic expression in a large Noonan syndrome family segregating a novel SOS1 mutation
We report on a novel pathogenic mutation in the SOS1 gene and a large clinical spectrum in a NS family with ten genetically confirmed affected individuals. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 8, 2017 Category: Genetics & Stem Cells Authors: Doroth ée C. van Trier, Tuula Rinne, Kees Noordam, Jos M. Draaisma, Ineke van der Burgt Tags: ORIGINAL ARTICLE Source Type: research

FOXP1 haploinsufficiency: Phenotypes beyond behavior and intellectual disability?
The forkhead box (FOX) transcription factors have roles in development, carcinogenesis, metabolism, and immunity. In humans FOXP1 mutations have been associated with language and speech defects, intellectual disability, autism spectrum disorder, facial dysmorphisms, and congenital anomalies of the kidney and urinary tract. In mice, Foxp1 plays critical roles in development of the spinal motor neurons, lymphocytes, cardiomyocytes, foregut, and skeleton. We hypothesized therefore that mutations of FOXP1 affect additional tissues in some humans. Supporting this hypothesis, we describe two individuals with novel variants of FO...
Source: American Journal of Medical Genetics Part A - September 8, 2017 Category: Genetics & Stem Cells Authors: Angela Myers, Christ èle du Souich, Connie L. Yang, Lior Borovik, Jill Mwenifumbo, Rosemarie Rupps, CAUSES Study, Anna Lehman, Cornelius F. Boerkoel Tags: CLINICAL REPORT Source Type: research

Testing the face shape hypothesis in twins discordant for nonsyndromic orofacial clefting
Nonsyndromic orofacial clefts (OFCs) are complex traits characterized by multifactorial inheritance and wide phenotypic variability. Numerous studies have shown subtle differences in the faces of unaffected relatives from cleft families compared to controls, the implication being that such outward differences are an incomplete expression reflecting an underlying genetic predisposition. Twins discordant for OFCs provide a unique opportunity to further test this idea, as the unaffected co‐twin shares on average 50% (for dizygotic twins) and 100% (for monozygotic twins) of the genetic risk factors as the affected twin. We u...
Source: American Journal of Medical Genetics Part A - September 8, 2017 Category: Genetics & Stem Cells Authors: Jasmien Roosenboom, Karlijne Indencleef, Greet Hens, Hilde Peeters, Kaare Christensen, Mary L. Marazita, Peter Claes, Elizabeth J. Leslie, Seth M. Weinberg Tags: ORIGINAL ARTICLE Source Type: research

Two novel mutations in XYLT2 cause spondyloocular syndrome
We report on two new patients with spondyloocular syndrome. Both patients harbor novel homozygous mutations in the XYLT2 gene. The patients present severe generalized osteoporosis, multiple fractures, short stature, cataract, and mild hearing impairment. XYLT2 mutations have been identified in spondyloocular syndrome, however only five mutations have been reported previously. These two patients with novel mutations extend the phenotypic and genotypic spectrum of spondyloocular syndrome. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 8, 2017 Category: Genetics & Stem Cells Authors: Fulya Taylan, Zehra Yava ş Abalı, Nina Jäntti, Nilay Güneş, Feyza Darendeliler, Firdevs Baş, Şükran Poyrazoğlu, Nevbahar Tamçelik, Beyhan Tüysüz, Outi Mäkitie Tags: CLINICAL REPORT Source Type: research

Congenital heart defects in molecularly proven Kabuki syndrome patients
In conclusion, a CHD is detected in 70% of patients with KMT2D (MLL2) pathogenic variants, most commonly left‐sided obstructive lesions, including multiple left‐sided obstructions similar to those observed in the spectrum of the Shone complex, and septal defects. Clinical management of Kabuki syndrome should include echocardiogram at the time of diagnosis, with particular attention to left‐sided obstructive lesions and mitral anomalies, and annual monitoring for aortic arch dilatation. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 8, 2017 Category: Genetics & Stem Cells Authors: Maria Cristina Digilio, Maria Gnazzo, Francesca Lepri, Maria Lisa Dentici, Elisa Pisaneschi, Anwar Baban, Chiara Passarelli, Rossella Capolino, Adriano Angioni, Antonio Novelli, Bruno Marino, Bruno Dallapiccola Tags: ORIGINAL ARTICLE Source Type: research

Novel homozygous missense mutation in NT5C2 underlying hereditary spastic paraplegia SPG45
SPG45 is a rare form of autosomal recessive spastic paraplegia associated with mental retardation. Detailed phenotyping and mutation analysis was undertaken in three individuals with SPG45 from a consanguineous family of Arab Muslim origin. Using whole‐exome sequencing, we identified a novel homozygous missense mutation in NT5C2 (c.1379T>C; p.Leu460Pro). Our data expand the molecular basis of SPG45, adding the first missense mutation to the current database of nonsense, frameshift, and splice site mutations. NT5C2 mutations seem to have a broad clinical spectrum and should be sought in patients manifesting either as u...
Source: American Journal of Medical Genetics Part A - September 8, 2017 Category: Genetics & Stem Cells Authors: Rachel Straussberg, Alexandros Onoufriadis, Osnat Konen, Yasmin Zouabi, Lior Cohen, John Y.W. Lee, Chao ‐Kai Hsu, Michael A. Simpson, John A. McGrath Tags: CLINICAL REPORT Source Type: research

Confirmation of an ARID2 defect in SWI/SNF ‐related intellectual disability
We present a 4‐year‐old girl with delayed neuromotor development, short stature of prenatal onset, and specific behavioral and craniofacial features harboring an intragenic deletion in the ARID2 gene. The phenotype confirmed the major features of the recently described ARID2‐related intellectual disability syndrome. However, our patient showed overlapping features with Nicolaides‐Baraitser syndrome and Coffin‐Siris syndrome, providing further arguments to reclassify these disorders as “SWI/SNF‐related intellectual disability syndromes.” (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 8, 2017 Category: Genetics & Stem Cells Authors: Ruben Van Paemel, Pauline De Bruyne, Saskia van der Straaten, Marleen D'hondt, Urlien Fr änkel, Annelies Dheedene, Björn Menten, Bert Callewaert Tags: CLINICAL REPORT Source Type: research

Survival beyond the perinatal period expands the phenotypes caused by mutations in GLE1
Mutations in GLE1 underlie Lethal Congenital Contracture syndrome (LCCS) and Lethal Arthrogryposis with Anterior Horn Cell Disease (LAAHD). Both LCCS and LAAHD are characterized by reduced fetal movements, congenital contractures, and a severe form of motor neuron disease that results in fetal death or death in the perinatal period, respectively. We identified bi‐allelic mutations in GLE1 in two unrelated individuals with motor delays, feeding difficulties, and respiratory insufficiency who survived beyond the perinatal period. Each affected child had missense variants predicted to result in amino acid substitutions near...
Source: American Journal of Medical Genetics Part A - September 8, 2017 Category: Genetics & Stem Cells Authors: Edith Said, Jessica X. Chong, Maja Hempel, Jonas Denecke, Paul Soler, Tim Strom, Deborah A. Nickerson, Christian Kubisch, , Michael J. Bamshad, Davor Lessel Tags: CLINICAL REPORT Source Type: research

A novel missense variant in the GLI3 zinc finger domain in a family with digital anomalies
Mutations in GLI3, which encodes a transcription factor of the Hedgehog signaling pathway, cause several developmental anomalies linked to inappropriate tissue patterning. Here, we report a novel missense variant in the fifth zinc finger domain of GLI3 (c.1826G>A; p.(Cys609Tyr)) initially identified in a proband with preaxial polydactyly type IV, developmental delay, sensorineural hearing loss, skeletal, and genitourinary anomalies. Additional family members exhibited various digital anomalies such as preaxial polydactyly, syndactyly, and postaxial polydactyly either in isolation or combined. Functional studies of Cys60...
Source: American Journal of Medical Genetics Part A - September 8, 2017 Category: Genetics & Stem Cells Authors: J. Aaron Crapster, Louanne Hudgins, James K. Chen, Natalia Gomez ‐Ospina Tags: CLINICAL REPORT Source Type: research

De novo SETD5 loss ‐of‐function variant as a cause for intellectual disability in a 10‐year old boy with an aberrant blind ending bronchus
This report adds to publications describing intragenic mutations in SETD5 and supports the assertion that de novo LoF mutations in SETD5 present with an overlapping but distinct phenotype in comparison with 3p25 microdeletion syndromes. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - September 1, 2017 Category: Genetics & Stem Cells Authors: Claire Green, Joshua Willoughby, , Meena Balasubramanian Tags: CLINICAL REPORT Source Type: research

HLX is a candidate gene for a pattern of anomalies associated with congenital diaphragmatic hernia, short bowel, and asplenia
We describe two fetuses with a unique pattern of multiple congenital anomalies, including diaphragmatic hernia, short bowel and asplenia, born to first‐cousin parents. Whole exome sequencing showed that both were homozygous for a missense variant, c.950A>C, predicting p.Asp317Ala, in the H.20‐Like Homeobox 1 (HLX1) gene. HLX is a homeobox transcription factor gene which is relatively conserved across species. Hlx homozygous null mice have a short bowel and reduced muscle cells in the diaphragm, closely resembling the anomalies in the two fetuses and we therefore suggest that the HLX mutation in this family could exp...
Source: American Journal of Medical Genetics Part A - September 1, 2017 Category: Genetics & Stem Cells Authors: Sandra A. Farrell, Sandi Sodhi, Christian R. Marshall, Andrea Guerin, Anne Slavotinek, Tara Paton, Karen Chong, Wilma L. Sirkin, Stephen W. Scherer, F élix‐Antoine Bérubé‐Simard, Nicolas Pilon Tags: CLINICAL REPORT Source Type: research

Treating pediatric neuromuscular disorders: The future is now
Pediatric neuromuscular diseases encompass all disorders with onset in childhood and where the primary area of pathology is in the peripheral nervous system. These conditions are largely genetic in etiology, and only those with a genetic underpinning will be presented in this review. This includes disorders of the anterior horn cell (e.g., spinal muscular atrophy), peripheral nerve (e.g., Charcot–Marie–Tooth disease), the neuromuscular junction (e.g., congenital myasthenic syndrome), and the muscle (myopathies and muscular dystrophies). Historically, pediatric neuromuscular disorders have uniformly been conside...
Source: American Journal of Medical Genetics Part A - September 1, 2017 Category: Genetics & Stem Cells Authors: James J. Dowling, Hernan D. Gonorazky, Ronald D. Cohn, Craig Campbell Tags: RESEARCH REVIEW Source Type: research

Pharmacological interventions to improve cognition and adaptive functioning in Down syndrome: Strides to date
Although an increasing number of clinical trials have been developed for cognition in Down syndrome, there has been limited success to date in identifying effective interventions. This review describes the progression from pre‐clinical studies with mouse models to human clinical trials research using pharmacological interventions to improve cognition and adaptive functioning in Down syndrome. We also provide considerations for investigators when conducting human clinical trials and describe strategies for the pharmaceutical industry to advance the field in drug discovery for Down syndrome. Future research focusing on ear...
Source: American Journal of Medical Genetics Part A - September 1, 2017 Category: Genetics & Stem Cells Authors: Sarah J. Hart, Jeannie Visootsak, Paul Tamburri, Patrick Phuong, Nicole Baumer, Maria ‐Clemencia Hernandez, Brian G. Skotko, Cesar Ochoa‐Lubinoff, Xavier Liogier D'Ardhuy, Priya S. Kishnani, Gail A. Spiridigliozzi Tags: RESEARCH REVIEW Source Type: research

Genotypic ‐phenotypic features and enzyme replacement therapy outcome in patients with mucopolysaccharidosis VI from Turkey
Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disorder (LSD) characterized by a chronic, progressive course with multiorgan involvement. In our study, clinical, biochemical, molecular findings, and response to enzyme replacement therapy (ERT) for at least 6 months were evaluated in 20 patients with MPS VI. Treatment effects on clinical findings such as liver and spleen sizes, cardiac and respiratory parameters, visual and auditory changes, joints’ range of motions, endurance tests and changes in urinary glycosaminoglycan excretions, before and after ERT were analyzed. ERT caused increased physical end...
Source: American Journal of Medical Genetics Part A - September 1, 2017 Category: Genetics & Stem Cells Authors: Mustafa K ılıç, Ali Dursun, Turgay Coşkun, Ayşegül Tokatlı, Rıza K. Özgül, Didem Yücel‐Yılmaz, Mehmet Karaca, Deniz Doğru, Dursun Alehan, Sibel Kadayıfçılar, Aydan Genç, Handan Turan‐Dizdar, Burhanettin Gönüldaş, Sema Savcı, Melda Tags: ORIGINAL ARTICLE Source Type: research

Challenges in measuring the effects of pharmacological interventions on cognitive and adaptive functioning in individuals with Down syndrome: A systematic review
We systematically reviewed the measures used in pharmaceutical trials in children/adults with Down syndrome without dementia. Our purpose was to identify developmentally appropriate outcome measures capable of detecting changes in cognitive and adaptive functioning in this population. Eleven studies were included and used diverse outcome measures across the domains of language, memory, attention, behavior, and executive/adaptive functioning. Our results highlight the challenges in selecting measures capable of capturing improvements in pharmaceutical trials in individuals with DS. We offer suggestions to enhance future res...
Source: American Journal of Medical Genetics Part A - August 31, 2017 Category: Genetics & Stem Cells Authors: Lori A. Keeling, Gail A. Spiridigliozzi, Sarah J. Hart, Jane A. Baker, Harrison N. Jones, Priya S. Kishnani Tags: RESEARCH REVIEW Source Type: research

Encephalopathy caused by novel mutations in the CMP ‐sialic acid transporter, SLC35A1
Transport of activated nucleotide‐sugars into the Golgi is critical for proper glycosylation and mutations in these transporters cause a group of rare genetic disorders termed congenital disorders of glycosylation. We performed exome sequencing on an individual with a profound neurological presentation and identified rare compound heterozygous mutations, p.Thr156Arg and p.Glu196Lys, in the CMP‐sialic acid transporter, SLC35A1. Patient primary fibroblasts and serum showed a considerable decrease in the amount of N‐ and O‐glycans terminating in sialic acid. Direct measurement of CMP‐sialic acid transport into the G...
Source: American Journal of Medical Genetics Part A - August 30, 2017 Category: Genetics & Stem Cells Authors: Bobby G. Ng, Carla G. Asteggiano, Martin Kircher, Kati J. Buckingham, Kimiyo Raymond, Deborah A. Nickerson, Jay Shendure, Michael J. Bamshad, , Matthias Ensslen, Hudson H. Freeze Tags: ORIGINAL ARTICLE Source Type: research

Congenital neurodevelopmental anomalies in pediatric and young adult cancer
Congenital anomalies that are diagnosed in at least 120,000 US infants every year are the leading cause of infant death and contribute to disability and pediatric hospitalizations. Several large‐scale epidemiologic studies have provided substantial evidence of an association between congenital anomalies and cancer risk in children, suggesting potential underlying cancer‐predisposing conditions and the involvement of developmental genetic pathways. Electronic medical records from 1,107 pediatric, adolescent, and young adult oncology patients were reviewed. The observed number (O) of congenital anomalies among children w...
Source: American Journal of Medical Genetics Part A - August 29, 2017 Category: Genetics & Stem Cells Authors: Jeannette R. Wong ‐Siegel, Kimberly J. Johnson, Katie Gettinger, Nicole Cousins, Nicole McAmis, Ashley Zamarione, Todd E. Druley Tags: ORIGINAL ARTICLE Source Type: research

Factors related to home health ‐care transition in trisomy 13
This study has shown that gestational age, occipitofrontal circumference Z score at birth, and the presence of CHD are helpful prognostic factors for determining treatment strategy in patients with T13. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - August 29, 2017 Category: Genetics & Stem Cells Authors: Yuma Kitase, Masahiro Hayakawa, Taiki Kondo, Akiko Saito, Takashi Tachibana, Makoto Oshiro, Kuniko Ieda, Eiko Kato, Yuichi Kato, Tetsuo Hattori, Seiji Hayashi, Masatoki Ito, Reina Hyodo, Yukako Muramatsu, Yoshiaki Sato Tags: ORIGINAL ARTICLE Source Type: research

De novo pathogenic variant in TUBB2A presenting with arthrogryposis multiplex congenita, brain abnormalities, and severe developmental delay
We report the sixth individual with a de novo heterozygous TUBB2A pathogenic variant, who presented with a severe neurological phenotype along with unique features of arthrogryposis multiplex congenita, optic nerve hypoplasia, dysmorphic facial features, and vocal cord paralysis, thereby expanding the gene‐related phenotype. (Source: American Journal of Medical Genetics Part A)
Source: American Journal of Medical Genetics Part A - August 25, 2017 Category: Genetics & Stem Cells Authors: Resham Ejaz, Anath C. Lionel, Susan Blaser, Susan Walker, Stephen W. Scherer, Riyana Babul ‐Hirji, Christian R. Marshall, Dimitri J. Stavropoulos, David Chitayat Tags: CLINICAL REPORT Source Type: research

A new CUL4B variant associated with a mild phenotype and an exceptional pattern of leukoencephalopathy
Cabezas type of X‐linked syndromic intellectual disability (MRXSC; MIM300354) is a rare X‐linked recessive intellectual disability characterized primarily by intellectual disability, short stature, hypogonadism, and gait abnormalities. It is caused by a wide spectrum of hemizygous variants in CUL4B. In a 10‐year‐old boy with an exceptional leukoencephalopathy pattern, we identified a new missense variant p.Leu329Gln in CUL4B using “Mendeliome” sequencing. However, his phenotype does not include the severe characteristics currently known for MRXSC. We discuss the divergent phenotype and propose a potenti...
Source: American Journal of Medical Genetics Part A - August 17, 2017 Category: Genetics & Stem Cells Authors: Susann Weissbach, Marie ‐Christine Reinert, Janine Altmüller, Ralph Krätzner, Holger Thiele, Thorsten Rosenbaum, Peter Nürnberg, Jutta Gärtner Tags: CLINICAL REPORT Source Type: research

The facial morphology in Down syndrome: A 3D comparison of patients with and without obstructive sleep apnea
Obstructive sleep apnea (OSA) occurs at a high prevalence in patients with Down syndrome (DS). A polysomnogram, which is often cumbersome and challenging, remains the gold standard method of diagnosing OSA. OSA in patients with DS is often attributed to skeletal and soft‐tissue structural alterations that are characteristic of the DS phenotype; as such, we hypothesized that assessing anthropometric facial measurements may be predictive of OSA in patients with DS. We used the 3dMDface sterophotography system to capture and create 3D facial images, and we subsequently identified facial landmarks using a single, experienced...
Source: American Journal of Medical Genetics Part A - August 17, 2017 Category: Genetics & Stem Cells Authors: Yasas S. N. Jayaratne, Ibrahim Elsharkawi, Eric A. Macklin, Lauren Voelz, Gil Weintraub, Dennis Rosen, Brian G. Skotko Tags: ORIGINAL ARTICLE Source Type: research

Stakeholders in psychiatry and their attitudes toward receiving pertinent and incident findings in genomic research
This study aims to gain more knowledge on the attitudes among potential research participants and health professionals toward receiving pertinent and incidental findings. A cross‐sectional online survey was developed to investigate the attitudes among research participants toward receiving genomic findings. A total of 2,637 stakeholders responded: 241 persons with mental disorders, 671 relatives, 1,623 blood donors, 74 psychiatrists, and 28 clinical geneticists. Stakeholders wanted both pertinent findings (95%) and incidental findings (91%) to be made available for research participants. The majority (77%) stated that re...
Source: American Journal of Medical Genetics Part A - August 17, 2017 Category: Genetics & Stem Cells Authors: Anna Sundby, Merete W. Boolsen, Kristoffer S. Burgdorf, Henrik Ullum, Thomas F. Hansen, Anna Middleton, Ole Mors Tags: ORIGINAL ARTICLE Source Type: research

Prenatal presentation of Mabry syndrome with congenital diaphragmatic hernia and phenotypic overlap with Fryns syndrome
We report on a family in which initial features were compatible with Fryns syndrome. The first sibling was a stillborn female with a left diaphragmatic hernia (DH). Her clinical features overlapped with Fryns syndrome. The second pregnancy, a male fetus, was followed for polyhydramnios, hypoplastic mandible, mild enlargement of the fetal bladder, hydronephrosis, and rocker bottom foot deformities. He had facial features similar to his sibling and a large cleft of the secondary palate, small jaw, and secundum atrial septal defect. He underwent surgical repair of imperforate anus, intestinal malrotation, and placement of muc...
Source: American Journal of Medical Genetics Part A - August 17, 2017 Category: Genetics & Stem Cells Authors: Kara K. Reynolds, Jane Juusola, Gregory M. Rice, Philip F. Giampietro Tags: CLINICAL REPORT Source Type: research