Identification of a novel mutation in patients with medium-chain acyl-CoA dehydrogenase deficiency

A novel mutation was identified in two unrelated patients with medium-chain acyl-CoA dehydrogenase deficiency. First, a 19-year-old Caucasian female presented with a devastating illness, resulting in sudden death in adulthood which is unusual. The second patient, now a 3.5-year-old male, presented at 17 months of age with a hypoglycemic seizure and dehydration. Sequence analysis revealed a novel mutation G617T in exon 8 resulting in an arginine to leucine substitution at codon 206 (R206L). Both patients were compound heterozygous for this G617T and the common mutation A985G.     

Renpenning syndrome in an Indian patient

Renpenning syndrome is one of the well‐characterized causes of X‐linked intellectual disability and is associated with microcephaly and various visceral malformations. Face is considered characteristic but the dysmorphism is subtle. Here we report an Indian adult with a very lean habitus, progressive atrophy of the upper back muscles, microcephaly, loss of cervical lordosis, and upper thoracic scoliosis. Using whole‐exome sequencing, a hemizygous deletion was identified in PQBP1 that leads to a frameshift and premature termination of translation. The loss of normal curvatures of cervical and upper thoracic spine due to muscular atrophy is a characteristic feature, though it may be age dependent.     

Identification of a novel mutation of CFTR gene in a Korean patient with cystic fibrosis

Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in Caucasians, but rare in Asians. The mutations of cystic fibrosis transmembrane conductance regulator (CFTR) gene are responsible for CF. To date, less than 5 cases of CF have been reported and a few of them diagnosed based on the genotype of the CFTR gene in Korea. We encountered a 4-month-old Korean infant with CF and the diagnosis was confirmed by CFTR gene mutation analysis. The patient underwent surgical operation, due to meconium ileus at birth. He suffered by recurrent respiratory infections, failure to thrive, fatty liver with hepatomegaly, and cholestasis. The mutations of the CFTR gene were identified in the patient and his parents. The patient was a compound heterozygote with a nonsense mutation of c.263T>G, resulting in an amino acid change of p.Leu88X in exon 3. It was previously described in a Korean patient with CF. The other is a novel mutation; c.2089-2090insA mutation (p.Arg697LysfsX33) in exon 13. The mutation c.263T>G was inherited from his father, and the c.2089-2090insA mutation from his mother. Respiratory infection was recovered by supportive care, and cholestasis was improved slowly with sufficient feeding and supplementation of pancreatic exocrine enzymes. He is 19- month old now and shows catch-up growth. We report a novel CFTR mutation in a Korean infant with CF.     

A novel nonsense mutation of the PEPD gene in a Japanese patient with prolidase deficiency

A nonsense mutation at amino acid residue 184 in the human peptidase D (PEPD) gene caused the production of a truncated polypeptide. Characterizing molecular defects in patients provides clues to elucidate the relationship between the phenotype and the genotype. Received: November 8, 1999 / Accepted: November 24, 1999     

Identification of a novel mutation in the MAFB gene in a pediatric patient with multicentric carpotarsal osteolysis syndrome using next-generation sequencing

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare form of skeletal dysplasia characterized by progressive bone resorption, in the carpal and tarsal bones. Patients may develop chronic kidney disease, which eventually advances to end-stage renal disease (ESRD). Both sporadic and familial cases of autosomal-dominant inheritance are reported in literature. Here, we report a case of a 10.5-year-old boy who presented with CKD stage V, and who suffered from bone deformities and difficulty in walking at a younger age. He was diagnosed with MCTO and subjected to genetic analysis. We identified a novel mutation (NM_005461.5:c.173C > G) in the exon 1 of MAFB using next-generation sequencing. However, the mutation was not detected in his asymptomatic parents or siblings. This novel heterozygous mutation has not been reported previously. Our results show that the new mutation broadens the spectrum of disease phenotypes. This mutation may be helpful to confirm the potential cases of MCTO, which although can be identified through radiographic findings, stand a high chance of being misdiagnosed as rheumatological disease or as a metabolic bone disease secondary to CKD.     

Extracranial midline defects in a patient with craniofrontonasal syndrome with a novel EFNB1 mutation

We report a female patient with craniofrontonasal syndrome (CFNS) who in addition showed other cranial and extracranial midline defects including partial corpus callosum agenesis, ocular melanocytosis, pigmentary glaucoma, duplex collecting system, uterus didelphys, and septate vagina. She was found to have a novel pathogenic variant in exon 5 of EFNB1, c.646G>T (p.Glu216*) predicted to cause premature protein truncation. From our review, we found at least 39 published CFNS patients with extracranial midline defects, comprising congenital diaphragmatic hernia, congenital heart defects, umbilical hernia, hypospadias, and less frequently, sacrococcygeal teratomas, and internal genital anomalies in females. These findings support that the EFNB1 mutations have systemic consequences disrupting morphogenetic events at the extracranial midline. Though these are not rigorously included as midline defects, we found at least 10 CFNS patients with congenital anomalies of the kidney and urinary tract, all females. Additionally, uterus didelphys and ocular melanocytosis observed in our patient are proposed also as a previously unreported EFNB1‐related midline defects. In addition, this case may be useful for considering the intentional search for genitourinary anomalies in future patients with CFNS, which will be helpful to define their frequency in this entity.     

完全型雄激素不敏感综合征雄激素受体基因突变的鉴定与分析

目的 对l例完全型雄激素不敏感综合征(complete androgen insensitivity syndrome,CAIS)患者的雄激素受体(androgen receptor,AR)基因进行分析,寻找潜在的突变位点,并进一步分析其发病原因.方法 提取患者外周血全基因组DNA,扩增位于X染色体AR基因8个外显子及邻近外显子与内含子剪切位点DNA序列,对扩增产物直接进行DNA序列测定,与GenBank中的基因序列进行比对.结果 该患者AR基因在第6外显子核苷酸序列3507位点缺失一个碱基C而引起移码突变,致使在第808位密码子出现终止密码子(TGA)使得翻译提前终止形成截短的雄激素受体蛋白.该突变可能诱导雄激素受体结合能力发生功能上的变异,导致CAIS的发生.结论 AR基因第6外显子核苷酸序列3507位点缺失碱基C引起的移码突变是一种导致CAIS新的基因突变方式,该研究丰富了AR基因突变谱,为了解CAIS的发病机制提供了新的依据.     

Burkitt lymphoma in a patient with Kabuki syndrome carrying a novel KMT2D mutation

Kabuki syndrome (KS) is an extremely rare genetic disorder, mainly caused by germline mutations at specific epigenetic modifier genes, including KMT2D. Because the tumor suppressor gene KMT2D is also frequently altered in many cancer types, it has been suggested that KS may predispose to the development of cancer. However, KS being a rare disorder, few data are available on the incidence of cancer in KS patients. Here, we report the case of a 5‐year‐old boy affected by KS who developed Burkitt lymphoma (BL). Genetic analysis revealed the presence of a novel heterozygous mutation in the splice site of the intron 4 of KMT2D gene in both peripheral blood‐extracted DNA and tumour cells. In addition, the tumour sample of the patient was positive for the classical somatic chromosomal translocation t(8;14) involving the c‐MYC gene frequently identified in BL. We propose that the mutated KMT2D gene contributes to the development of both KS and BL observed in our patient and we suggest that strict surveillance must be performed in KS patients.