American Journal Of Medical Genetics
American Journal of Medical Genetics Part A
Wiley Online Library : American Journal of Medical Genetics Part A

  • A 7q21.11 microdeletion presenting with apparent intellectual disability without epilepsy
  • Sleep-disordered breathing and its management in children with achondroplasia
    Sleep-disordered breathing is a common feature in children with achondroplasia. The aim of our study was to review the poly(somno)graphic (P(S)G) findings and consequent treatments in children with achondroplasia followed in the national reference center for skeletal dysplasia. A retrospective review of the clinical charts and P(S)G of 43 consecutive children (mean age 3.9 ± 3.5 years) with achondroplasia seen over a period of 2 years was performed. Twenty four (59%) children had obstructive sleep apnea (OSA). Thirteen children had an obstructive apnea-hypopnea index (OAHI) < 5/hr, four had an OAHI between 5 and 10/hr, and seven had an OAHI ≥ 10/hr. Ten of the 15 children who had previous upper airway surgery still had an abnormal P(S)G. All the patients with an AHI ≥ 10/hr were under 7 years of age and none had a prior tonsillectomy. The children who underwent adeno-tonsillectomy, coupled in most cases with turbinectomy, were significantly older (mean age 7.5 ± 3.5 vs. 3.5 ± 1.7 years old, P = 0.015) and had significantly better P(S)G results than those who underwent only adeno-turbinectomy. No correlation was observed between the mean AHI value at the baseline P(S)G and the type of academic course (standard, supported or specialized). In conclusion, OSA is common in children with achondroplasia. The observation of a reduced prevalence of OSA after (adeno-)tonsillectomy is in favor of this type of surgery when possible.

  • Timothy syndrome 1 genotype without syndactyly and major extracardiac manifestations
    Timothy syndrome 1 (TS1) is a rare genetic disorder characterized by multisystem abnormalities including QT prolongation, congenital heart defects, facial dysmorphism, episodic hypoglycemia, and neurological symptoms. A morphological hallmark of TS1 is syndactyly, present in all cases. TS1 is caused by the canonical p.Gly406Arg mutation in the alternatively spliced exon 8A in the CACNA1C gene, encoding for the main cardiac L-type calcium channel. A variant case of TS1 is reported. The proband had intermittent fetal bradycardia with heart rate of 72 bpm. On the first day of life bradycardia due to 2:1 atrioventricular (AV) block and marked QTc prolongation of 600 ms was noted. On medical therapy with propranolol and mexiletine 1:1 AV conduction returned with QTc prolongation of 470–580 ms. The patient lacked other extracardiac manifestations, most importantly syndactyly, neurological complications or autism. On genetic analysis, the canonical TS1 causing mutation, p.Gly406Arg in exon 8A of the CACNA1C gene was detected. The CACNA1C p.Gly406Arg variant was not present in the parents, but was detected in different DNA samples of the index patient. Our case highlight further phenotypic variability in TS. Most importantly, it underlines that the lack of syndactyly does not exclude the presence of a TS1 genotype. © 2017 Wiley Periodicals, Inc.

  • In this issue
  • Publication schedule for 2017
  • 1q21.3 deletion involving GATAD2B: An emerging recurrent microdeletion syndrome
    GATAD2B gene is involved in chromatin modification and transcription activity. Loss-of-function mutations of GATAD2B have recently been defined to cause a recognizable syndrome with intellectual disability (ID). Human TPM3 gene encoding thin filament protein is associated with myopathies. Both genes are located on chromosome 1q21.3. We herein report an infant with feeding difficulty, developmental delay, hypotonia, and dysmorphic features including small palpebral fissures, telecanthus, sparse hair and eyebrow, cup-shaped ears, and clinodactyly. Karyotype was normal. Single nucleotide polymorphism array revealed a 1.06 Mb deletion of chromosome 1q21.3, which was confirmed to be de novo. The deleted region encompassed 35 genes, including three known disease-associated genes, namely GATAD2B, TPM3, and HAX1. We further identify and summarize seven additional patients with 1q21.3 microdeletion from literature review and clinical databases (DECIPHER, ISCA/ClinGen). Genomic location analysis of all eight patients revealed different breakpoints and no segmental duplication, indicating that non-homologous end joining is a likely mechanism underlying this particular microdeletion. This data suggests that 1q21.3 microdeletion is a recurrent microdeletion syndrome with distinguishable phenotypes, and loss of function of GATAD2B is the major contributor of the characteristic facies and ID. Additionally, the deletion of TPM3 warrants a risk of concomitant muscle disease in our patient. © 2017 Wiley Periodicals, Inc.

  • Atypical Angelman syndrome due to a mosaic imprinting defect: Case reports and review of the literature
    Angelman syndrome (AS) is characterized by severe intellectual disability, limited, or absent speech and a generally happy demeanor. The four known etiological mechanisms; deletions, uniparental disomy, imprinting defects, and UBE3A mutation all affect expression of the UBE3A gene at 15q11-q13. An atypical phenotype is seen in individuals who are mosaic for a chromosome 15q11-q13 imprinting defect on the maternal allele. These patients present with a milder phenotype, often with hyperphagia and obesity or non-specific intellectual disability. Unlike typical AS syndrome, they can have a vocabulary up to 100 words and speak in sentences. Ataxia and seizures may not be present, and the majority of individuals do not have microcephaly. Here we review the current literature and present three individuals with atypical AS caused by a mosaic imprinting defect to demonstrate why DNA methylation analysis at the SNRPN locus needs to be considered in a broader clinical context. © 2017 Wiley Periodicals, Inc.

  • American college of medical genetics and genomics updates secondary findings guidelines
  • The recurrent PPP1CB mutation p.Pro49Arg in an additional Noonan-like syndrome individual: Broadening the clinical phenotype
    We report on a 12-year-old Brazilian boy with the p.Pro49Arg mutation in PPP1CB, a novel gene associated with RASopathies. This is the fifth individual described, and the fourth presenting the same variant, suggesting a mutational hotspot. Phenotypically, he also showed the same hair pattern—sparse, thin, and with slow growing—, similar to the typical ectodermal finding observed in Noonan syndrome-like disorder with loose anagen hair. Additionally, he presented craniosynostosis, a rare clinical finding in RASopathies. This report gives further support that this novel RASopathy—PPP1CB-related Noonan syndrome with loose anagen hair—shares great similarity to Noonan syndrome-like disorder with loose anagen hair, and expands the phenotypic spectrum by adding the cranial vault abnormality. © 2017 Wiley Periodicals, Inc.

  • Constitutional bone impairment in Noonan syndrome
    Noonan syndrome (NS) is an autosomal dominant trait characterized by genotypic and phenotypic variability. It belongs to the Ras/MAPK pathway disorders collectively named Rasopathies or neurocardiofaciocutaneous syndromes. Phenotype is characterized by short stature, congenital heart defects, facial dysmorphisms, skeletal and ectodermal anomalies, cryptorchidism, mild to moderate developmental delay/learning disability, and tumor predisposition. Short stature and skeletal dysmorphisms are almost constant and several studies hypothesized a role for the RAS pathway in regulating bone metabolism. In this study, we investigated the bone quality assessed by phalangeal quantitative ultrasound (QUS) and the metabolic bone profiling in a group of patients with NS, to determine whether low bone mineralization is primary or secondary to NS characteristics. Thirty-five patients were enrolled, including 20 males (55.6%) and 15 females (44.5%) aged 1.0–17.8 years (mean 6.4 ± 4.5, median 4.9 years). Each patients was submitted to clinical examination, estimation of the bone age, laboratory assays, and QUS assessment. Twenty-five percent of the cohort shows reduced QUS values for their age based on bone transmission time. Bone measurement were adjusted for multiple factors frequently observed in NS patients, such as growth retardation, delayed bone age, retarded puberty, and reduced body mass index, potentially affecting bone quality or its appraisal. In spite of the correction attempts, QUS measurement indicates that bone impairment persists in nearly 15% of the cohort studied. Our results indicate that bone impairment in NS is likely primary and not secondary to any of the phenotypic traits of NS, nor consistent with metabolic disturbances. © 2017 Wiley Periodicals, Inc.


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