Genetics and Genomics of Congenital diseases

Virtually any disease is the result of the combined action of genes and environment, but the relative role of the genetic component may be large or small. Among disorders caused wholly or partly by genetic factors, three main types are recognized : chromosome disorder, single-gene defect, multifactorial disease with complex inheritance. In chromosome disorders, the defect is due to an excess or deficiency of genes located on entire chromosomes or chromosome segments. Single-gene defects are caused by pathogenic mutations in individual genes. The mutation may be present on both chromosomes of a pair or on only one chromosome of a pair. Single-gene defects often cause diseases that follow one of the classic inheritance patterns in families, autosomal recessive, autosomal dominant, or X-linked. Most such defects are rare, but single-gene disorders as a group are responsible for a significant proportion of disease and death. Multifactorial disease with complex inheritance describes the majority of diseases in which there is a genetic contribution, as evidenced by increased risk for disease in identical twins or close relatives of affected individuals, and yet the family history does not fit the inheritance patterns seen typically in single-gene defects. There appears to be no single error in the genetic information in many of these condition. Genetic counselors define and address the complex psychosocial issues associated with a genetic disorder in a family and provide psychologically oriented counseling to help individuals adapt and adjust to impact and implications of the disorder in the family. For this reason, genetic counseling may be most effectively accomplish through periodic contact with the family. In this article, I describe how genetics and genomics are applied to medical today

A case of generalized lymphatic anomaly causing skull-base leakage and bacterial meningitis

Generalized lymphatic anomaly (GLA) is a multifocal lymphatic malformation that affects the skin, thoracic viscera, and bones. A 7-year-old boy presented with fever and disturbance of consciousness, and bacterial meningitis was diagnosed. Computed tomography and magnetic resonance imaging revealed middle skull-base leakage due to lymphatic malformation. Past history included facial palsy due to cystic tumors in the right petrous bone 4 years before onset of meningitis. At that time, pericardial effusion had been found and GLA had been diagnosed by pericardial biopsy. He achieved complete recovery under intensive care with antibiotics and mechanical ventilation. At the 3-year follow-up, the patient was healthy with no recurrence of meningitis. We should consider GLA among the differential diagnoses for osteolytic diseases in the pediatric population

Age-related changes in a patient with Pelizaeus-Merzbacher disease by repeated 1H-MRS

Purpose: In this report, we describe a patient with Pelizaeus-Merzbacher disease (PMD) who underwent repeated evaluations by 1H-Magnetic resonance spectroscopy (MRS). Subject: The patient was given a definitive diagnosis of PMD based on genetic testing, which showed overlap of the proteolipid protein 1 (PLP1) gene. The control subjects for 1H-MRS consisted of healthy age-matched children. Methods: All measurements were performed with a clinical 3-tesla magnetic resonance imaging (MRI) system. For 1H-MRS, the center of a voxel was positioned in the right parietal lobe. 1H-MRS was performed when the patient was 2, 6, 14, and 25 months old. Results: The concentration of GABA in early childhood (2 months 1.72 mM, 6 months 2.15 mM) was increased compared with that in normal controls. However, his GABA concentration was normalized at 14 and 25 months. The concentrations of Ins were increased after 6 months. No remarkable changes were seen in the concentration of Cho at any time. Conclusion These results suggest that the changes in metabolite concentrations during growth may reflect the pathological state of PMD. Furthermore, the lack of a change in the Cho concentration may be useful for differentiating PMD from other demyelinating diseases

A 16q22.2-q23.1 deletion identified in a male infant with West syndrome

In partial monosomy of the distal part of chromosome 16q, abnormal facial features, intellectual disability (ID), and feeding dysfunction are often reported. However, seizures are not typical and the majority of them were seizure-free. Here we present the case of a 16q22.2-q23.1 interstitial deletion identified in a male patient with severe ID, facial anomalies including forehead protrusions and flat nose bridge, patent ductus arteriosus, bilateral vocal cord atresia treated by tracheotomy, and West syndrome, which were developed 10 months after birth. Although phenobarbital, sodium valproate (VPA), and zonisamide were not effective as monotherapies or combination therapies, the patient's epileptic seizures and electroencephalogram anomalies disappeared following combined therapy with lamotrigine and VPA. Although WW Domain Containing Oxidoreductase (WWOX), which is known as a cause of autosomal recessive epileptic encephalopathy, was included within the 6.8-Mb deleted region which identified by targeted panel sequencing and validated by chromosomal microarray analysis, no pathogenic variants were detected in the other allele of WWOX. Therefore, it is possible that other genes within or outside of the long deleted region or their interactions may cause West syndrome in this patient

Multi-delay arterial spin labeling brain magnetic resonance imaging study for pediatric autism

Introduction Arterial spin labeling (ASL) is a non-invasive magnetic resonance imaging (MRI) technique that can measure regional cerebral blood flow (rCBF) without radiation exposure. This study aimed to evaluate rCBF in individuals with autism and their age-matched controls, globally and regionally. Methods We performed ASL MRI (3T, pulsed-continuous ASL, 3 delayed ASL imaging sequences) for 33 patients with autism spectrum disorder (ASD) (average age: 7.3 years, range: 2-14 years). Nineteen children (average age: 8.6 years, range: 3-15 years) without ASD and intellectual delay were included as controls. Patients with morphological abnormalities detected on MRI were excluded. Objective analysis was performed with automatic region of interest analysis of the ASL results. The Mann-Whitney U test was used to compare the rCBF results between the groups. Results Compared to the controls, patients with ASD showed a statistically significant decrease in rCBF, respectively, in the insula [left, rCBF 51.8±9.5 mL/100 g/min (mean±SD) versus 59.9±9.8, p=0.0017; right, 51.2±10.1 versus 57.8±8.8, p=0.0354], superior parietal lobule (left, 44.6±8.4 versus 52.0±7.8, p=0.003), superior temporal gyrus (left, 50.0±8.6 versus 56.9±8.6, p=0.007; right, 49.5±8.4 versus 56.4±7.7, p=0.0058), and inferior frontal gyrus (left, 53.0±9.8 versus 59.3±9.9, p=0.0279), which are associated with the mirror neuron system. Conclusions We concluded that patients with ASD showed a statistically significant decline in CBF in regions associated with the mirror neuron system. The advantages of ASL MRI include low invasiveness (no radiation exposure) and short imaging time (approximately 5 min). Studies with larger sample sizes are required to establish the diagnostic value of ASL MRI for ASD

Novel COL5A2 mutation in Ehlers–Danlos syndrome

Ehlers–Danlos syndrome (EDS) is a group of inherited connective tissue disorders characterized by hyperextensible skin, joint hypermobility and soft tissue fragility. For molecular diagnosis, targeted exome sequencing was performed on a 9-year-old male patient who was clinically suspected to have EDS. The patient presented with progressive kyphoscoliosis, joint hypermobility and hyperextensible skin without scars. Ultimately, classical EDS was diagnosed by identifying a novel, mono-allelic mutation in COL5A2 [NM_000393.3(COL5A2_v001):c.682G>A, p.Gly228Arg]

Lowe syndrome caused by gloss deletion

Lowe syndrome (LS) is an X-linked disorder affecting the eyes, nervous system and kidneys, typically caused by missense or nonsense/frameshift OCRL mutations. We report a 6-month-old male clinically suspected to have LS, but without the Fanconi-type renal dysfunction. Using a targeted-exome sequencing-first approach, LS was diagnosed by the identification of a deletion involving 1.7 Mb at Xq25-q26.1, encompassing the entire OCRL gene and neighboring loci

A case of acute acalculous cholecystitis complicated by primary Epstein-Barr virus infection

Acute acalculous cholecystitis (AAC) is a rare complication of infectious mononucleosis (IM). An immunocompetent 6-year-old Japanese girl complained of epigastralgia during the course of IM. Ultrasonography (US) revealed a markedly thickened and sonolucent gallbladder wall. No gallstones were apparent. Antibodies against Epstein-Barr virus (EBV) confirmed primary EBV infection. Cytomegalovirus immunoglobulin M showed a false-positive result in the acute phase, probably due to cross-reaction to EBV nuclear antigen. We diagnosed her as AAC related with primary EBV infection. She recovered completely by conservative treatment. US should be performed in consideration of the possibility of AAC when a patient with IM complains of epigastralgia

The first Japanese MDPL case

Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome is a rare autosomal dominant disorder caused by heterozygous POLD1 mutations. To date, 13 patients affected by POLD1 mutation-caused MDPL have been described. We report a clinically undiagnosed 11-year-old male who noted joint contractures at 6 years of age. Targeted exome sequencing identified a known POLD1 mutation [NM_002691.3:c.1812_1814del, p.(Ser605del)] that diagnosed him as the first Japanese/East Asian MDPL case

Molecular diagnosis of an infant with TSC2/PKD1 contiguous gene syndrome

A 1-month-old Japanese infant with cardiac rhabdomyoma was diagnosed with TSC2/PKD1 contiguous gene syndrome by targeted panel sequencing with subsequent quantitative polymerase chain reaction that revealed gross monoallelic deletion, including parts of two genes: exons 19–42 of TSC2 and exons 2–46 of PKD1. Early molecular diagnosis can help to detect bilateral renal cyst formation and multidisciplinary follow-up of this multisystem disease