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Am J Med Genet A 2022 May 24. Epub 2022 May 24.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.

Am J Med Genet A 2022 May 21. Epub 2022 May 21.

Department of Developmental Paediatrics, Christian Medical College and Hospital, Vellore, India.

We report here two girls from different Indian families identified with novel variants in the AT Hook DNA Binding Motif Containing 1 gene (AHDC1) causing Xia-Gibbs syndrome. The diagnosis was made by clinical exome in both cases. Inconsistent dysmorphic features such as dolichocephaly in the first patient and brachycephaly in the second were observed. Read More

Am J Med Genet A 2022 May 20. Epub 2022 May 20.

Department of Medical Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

Maternal uniparental disomy of human chromosome 7 [upd(7)mat] is well-characterized as a cause of the growth disorder Silver-Russell syndrome (SRS). However, the causative gene is not currently known. There is growing evidence that molecular changes at the imprinted MEST region in 7q32. Read More

Am J Med Genet A 2022 May 19. Epub 2022 May 19.

Division of Nephrology, Dartmouth-Hitchcock Medical Center in Lebanon, Lebanon, New Hampshire, USA.

Am J Med Genet A 2022 May 17. Epub 2022 May 17.

Centre for Human Genetics, Biotech Park, Bangalore, Karnataka, India.

Epidermolysis bullosa simplex (EBS) with plectin mutations is a very rare subtype of EB usually associated with pyloric atresia (PA) or muscular dystrophy (MD). We report six unrelated children between ages 4 and 14 years from India with varied clinical manifestations. Only one had PA, and none has developed MD to date. Read More

Am J Med Genet A 2022 Jun;188(6):1656-1657

Am J Med Genet A 2022 Jun;188(6):1657-1658

Am J Med Genet A 2022 May 16. Epub 2022 May 16.

Invitae Corporation, San Francisco, California, USA.

Guidelines for variant interpretation include criteria for incorporating phenotype evidence, but this evidence is inconsistently applied. Systematic approaches to using phenotype evidence are needed. We developed a method for curating disease phenotypes as highly or moderately predictive of variant pathogenicity based on the frequency of their association with disease-causing variants. Read More

Am J Med Genet A 2022 May 14. Epub 2022 May 14.

Division of Medical Genetic, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.

Pathogenic variants in ACTA2, encoding smooth muscle α-actin, predispose to thoracic aortic aneurysms and dissections. ACTA2 variants altering arginine 179 predispose to a more severe, multisystemic disease termed smooth muscle dysfunction syndrome (SMDS; OMIM 613834). Vascular complications of SMDS include patent ductus arteriosus (PDA) or aortopulmonary window, early-onset thoracic aortic disease (TAD), moyamoya-like cerebrovascular disease, and primary pulmonary hypertension. Read More

Am J Med Genet A 2022 May 14. Epub 2022 May 14.

Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.

Alazami syndrome (AS) is an autosomal recessive condition characterized by the cardinal features of severe growth restriction, moderate to severe intellectual disability, and distinctive facial features. Biallelic pathogenic variants of the LARP7, encoding a chaperone of 7SK noncoding RNA, is implicated in this disease. There are <35 reported cases in the literature. Read More

Am J Med Genet A 2022 May 14. Epub 2022 May 14.

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

When a de novo balanced reciprocal translocation is identified in patients with multiple congenital abnormalities, attempts are often made to infer the relationship between the phenotype of the patient and genes in the proximity of the breakpoint. Here, we report a patient with intellectual disability, atrial septal defect, syndactyly, and cleft lip and palate who had an "apparently balanced" de novo reciprocal translocation t(4:18)(q31;q11.2) as well as a 7-Mb cryptic deletion spanning the HOXD cluster on chromosome 2q31 that was unrelated to the reciprocal translocation. Read More

Am J Med Genet A 2022 May 12. Epub 2022 May 12.

Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

Neurofibromatosis Type 1 (NF1) is a common genetic disorder frequently associated with cognitive deficits. Despite cognitive deficits being a key feature of NF1, the profile of such impairments in NF1 has been shown to be heterogeneous. Thus, we sought to quantitatively synthesize the extant literature on cognitive functioning in NF1. Read More

Am J Med Genet A 2022 May 11. Epub 2022 May 11.

Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, Japan.

Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal dominant genetic disorder characterized by soft connective tissue vulnerability due to dysfunction of Type III collagen and caused by the pathogenic variants in COL3A1 gene. In the era of next-generation sequencing, multiple genes including COL3A1 can be simultaneously analyzed, and among patients suffering from aortopathy even without any other clinical features suggestive of vEDS, pathogenic COL3A1 variants have been increasingly identified. Here, we briefly summarize the characteristics of 12 Japanese patients from 11 families with arteriopathy and pathogenic or likely pathogenic COL3A1 variants in our hospital. Read More

Am J Med Genet A 2022 May 11. Epub 2022 May 11.

GeneDx, Inc., Gaithersburg, Maryland, USA.

The pre-mRNA-processing factor 8, encoded by PRPF8, is a scaffolding component of a spliceosome complex involved in the removal of introns from mRNA precursors. Previously, heterozygous pathogenic variants in PRPF8 have been associated with autosomal dominant retinitis pigmentosa. More recently, PRPF8 was suggested as a candidate gene for autism spectrum disorder due to the enrichment of sequence variants in this gene in individuals with neurodevelopmental disorders. Read More

Am J Med Genet A 2022 May 10. Epub 2022 May 10.

Department of Pediatrics, Faculty of Medicine, Pediatric Genetics Unit, Hacettepe University, Ankara, Turkey.

Genetic skeletal disorders (GSDs) are clinically and etiologically heterogeneous group of disorders caused by abnormal growth and development of bone and/or cartilaginous tissues. Timely and accurate diagnosis is essential for prevention of significant comorbidities. In this study demographic, parental, prenatal and natal characteristics, and postnatal diagnostic distribution along with follow-up processes of 104 individuals with the finding of "short femur" detected in routine prenatal ultrasonography were evaluated. Read More

Am J Med Genet A 2022 May 9. Epub 2022 May 9.

Department of Endocrinology, Austin Health, Melbourne, Victoria.

Hypogonadism is the most frequent hormonal deficiency in individuals with Prader-Willi syndrome (PWS). This often necessitates testosterone treatment, but limited data are available to guide testosterone treatment in adult men with PWS. We aimed to evaluate the serum testosterone concentrations and adverse effects of testosterone treatment in individuals with PWS attending a specialist obesity management service. Read More

Am J Med Genet A 2022 May 5. Epub 2022 May 5.

Am J Med Genet A 2022 May 2. Epub 2022 May 2.

Institute of Medical Genetics and Genomics, Sir Gangaram Hospital, New Delhi, India.

Pontocerebellar hypoplasia (PCH) type 12 is a rare, perinatal lethal neurodegenerative genetic disorder caused by biallelic mutations in the COASY gene. Herein, we describe the clinical and neuroradiological profile of nine affected fetuses/neonates from five families identified with a common COASY: c.1486-3C>G biallelic variant. Read More

Am J Med Genet A 2022 May 2. Epub 2022 May 2.

Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Rome, Italy.

Crossed pulmonary arteries (CPAs) represent an uncommon anatomic variant, usually associated with some specific syndromes and conotruncal defects. This finding has been described in 22q11.2 Deletion Syndrome (22q11. Read More

Am J Med Genet A 2022 May 2. Epub 2022 May 2.

Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA.

Congenital nicotinamide adenine dinucleotide (NAD) deficiency disorders are associated with pathogenic variants in the genes NADSYN1, HAAO, and KYNU. These disorders overlap with the anomalies present in vertebral, anal, cardiac, tracheoesophageal, radial and renal, and limb anomalies (VATER/VACTERL) association and often result in premature death. Children who survive typically have developmental delays or intellectual disability. Read More

Am J Med Genet A 2022 May 2. Epub 2022 May 2.

Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

MYH7, encoding the myosin heavy chain sarcomeric β-myosin heavy chain, is a common cause of both hypertrophic and dilated cardiomyopathy. Additionally, families with left ventricular noncompaction cardiomyopathy (LVNC) and congenital heart disease (CHD), typically septal defects or Ebstein anomaly, have been identified to have heterozygous pathogenic variants in MHY7. One previous case of single ventricle CHD with heart failure due to a MYH7 variant has been identified. Read More

Am J Med Genet A 2022 Apr 29. Epub 2022 Apr 29.

Department of Pediatrics, Division of Medical Genetics, Helen DeVos Children's Hospital, Spectrum Health, Grand Rapids, Michigan, USA.

Pleiotropy is defined as the phenomenon of a single gene locus influencing two or more distinct phenotypic traits. However, nicotinamide adenine dinucleotide (NAD+) deficiency through diet alone can cause multiple or single malformations in mice. Additionally, humans with decreased NAD+ production due to changes in pathway genes display similar malformations. Read More

Am J Med Genet A 2022 Apr 28. Epub 2022 Apr 28.

Division of Pediatric Hematology/Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.

Beckwith-Wiedemann spectrum, Simpson-Golabi-Behmel syndrome, familial adenomatous polyposis and trisomy 18 are the most common congenital conditions associated with an increased incidence of hepatoblastoma (HB). In patients with these genetic disorders, screening protocols for HB are proposed that include periodic abdominal ultrasound and measurement of alpha-fetoprotein levels. Surveillance in these children may contribute to the early detection of HB and possibly improve their chances of overall survival. Read More

Am J Med Genet A 2022 Apr 22. Epub 2022 Apr 22.

Rady Children's Institute for Genomic Medicine, San Diego, California, USA.

Obstructive heart defects (OHDs) share common structural lesions in arteries and cardiac valves, accounting for ~25% of all congenital heart defects. OHDs are highly heritable, resulting from interplay among maternal exposures, genetic susceptibilities, and epigenetic phenomena. A genome-wide association study was conducted in National Birth Defects Prevention Study participants (N  = 3978; N  = 2507), investigating the genetic architecture of OHDs using transmission/disequilibrium tests (TDT) in complete case-parental trios (N  = 440; N  = 275) and case-control analyses separately in infants (N  = 1635; N  = 990) and mothers (case status defined by infant; N  = 1703; N  = 1078). Read More

Am J Med Genet A 2022 Apr 22. Epub 2022 Apr 22.

Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.

RAP1B is a RAS-superfamily small GTP-binding protein involved in numerous cell processes. Pathogenic gain-of-function variants in this gene have been associated with RAP1B-related syndromic thrombocytopenia, an ultrarare disorder characterized by hematologic abnormalities, neurodevelopmental delays, growth delay, and congenital birth defects including cardiovascular, genitourinary, neurologic, and skeletal systems. We report a 23-year-old male with a novel, de novo RAP1B gain-of-function variant identified on genome sequencing. Read More

Am J Med Genet A 2022 Apr 22. Epub 2022 Apr 22.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The cardiofacioneurodevelopmental syndrome (CFNDS) is characterized by craniofacial anomalies including bilateral cleft lip and palate, cardiac, skeletal, and neurodevelopmental features and additional variable manifestations. Whole-exome sequencing revealed homozygous loss-of-function variants in CCDC32 (alternative name: C15orf57) in both previously described patients. ccdc32 deletion in zebrafish suggests a ciliary contribution to the pathomechanism. Read More

Am J Med Genet A 2022 Apr 21. Epub 2022 Apr 21.

Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France.

Unique or multiple congenital facial skin polyps are features of several rare syndromes, from the most well-known Pai syndrome (PS), to the less recognized oculoauriculofrontonasal syndrome (OAFNS), encephalocraniocutaneous lipomatosis (ECCL), or Sakoda complex (SC). We set up a research project aiming to identify the molecular bases of PS. We reviewed 27 individuals presenting with a syndromic frontonasal polyp and initially referred for PS. Read More

Am J Med Genet A 2022 Apr 20. Epub 2022 Apr 20.

Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Genetically isolated populations that arise due to recent bottleneck events have reduced genetic variation reflecting the common set of founders. Increased genetic relatedness among members of isolated populations puts them at increased risk for some recessive disorders that are rare in outbred populations. To assess the burden on reproductive health, we compared frequencies of adverse reproductive outcomes between Amish couples who were both heterozygous carriers of a highly penetrant pathogenic or likely pathogenic variant and noncarrier couples from the same Amish community. Read More

Am J Med Genet A 2022 Apr 20. Epub 2022 Apr 20.

Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Proteus syndrome (PS) is a rare segmental overgrowth disorder caused by a mosaic activating variant in AKT1. The features of PS are often not present at birth but develop during the first few years of life. We describe a 55-year-old female, whose first symptom of overgrowth, a cerebriform connective tissue nevus, occurred at 19 years of age. Read More

Am J Med Genet A 2022 Apr 15. Epub 2022 Apr 15.

Department of Pediatrics, Southern Illinois University School of Medicine, Springfield, Illinois, USA.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder that commonly results in a dilated aorta, aneurysms, joint laxity, craniosynostosis, and soft skin that bruises easily. Neurodevelopmental abnormalities are uncommon in LDS. Two previous reports present a total of four patients with LDS due to pure 1q41 deletions involving TGFB2 (Gaspar et al. Read More