Case Reports in Genetics最新文献

Geroderma Osteodysplastica (GO) is a rare autosomal recessive connective tissue disease characterized by wrinkled skin and osteoporosis, two distinct aging-related features. A loss of function mutation in GORAB results in the disease. Immediately after birth, a cyanotic female neonate was found to have transposition of great vessels (TGV) that was corrected with an uneventful surgical recovery. The patient was noted to have wrinkled skin and hyperlaxity in her joints. After a complete nutritional and metabolic panel, in addition to karyotyping, imaging, skin histopathology analysis, and genetic testing she was found to have GO. We found two novel compound heterozygous mutations in GORAB: p.Asp236∗ and pAsp236Ala. This is the first study that reports the concurrent incidence of GO with TGV. The patient was started on bisphosphonates, which led to a reduction in the occurrence of fractures. An early diagnosis of GO is warranted to prevent or reduce bone density loss due to osteoporosis via initiation of bisphosphonate treatment. Whole exome sequencing remains the gold standard for diagnosing GO and ruling out phenotypically similar disorders.

Intellectual disability (ID) is seen in around 2.5% of global population and can vary from mild to severe and profound ID. There can be multiple affected family members if it is inherited, though many autosomal dominant ID cases would be due to de novo mutations are very less likely to recur in families. A confirmatory diagnosis is facilitated by genetic testing like chromosomal microarray and next generation sequencing. We describe here our cohort of 15 patients: children and adolescents with ID diagnosed by using sequencing technologies and parental segregation studies. Most of the variants identified were de novo variants and consistent with sporadic occurrence, and blended phenotypes were identified. Appropriate genetic counseling was performed and options for prenatal diagnosis were discussed. Thus, advanced sequencing technologies enable identification of likely causative de novo variants associated with intellectual disability and dysmorphism.

Nonsyndromic hereditary thoracic aortic aneurysm and dissection (TAAD) is an autosomal dominant disease; however, it is frequently difficult to identify the causative genes. We report in this study a 33-year-old Japanese male with TAAD (Stanford type A) that is complicated with severe aortic regurgitation. There was no family history of aortic diseases in the patient nor any specific clinical features suggestive of connective tissue diseases, such as Marfan syndrome. Genetic testing identified candidate causative variants in two different genes: MYLK (c.4819G > A, p.[Gly1607Ser]) and FBN1 (c.365G > A, p.[Arg122His]). Familial cosegregation analysis revealed that the novel de novo MYLK variant was present only in the proband, and the FBN1 variant was also found in his nonaffected mother, and thus the MYLK variant was classified as likely pathogenic. MYLK is a causative gene for nonsyndromic TAAD that requires careful management; however, the number of reports is limited. Accumulating data on the pathogenicity of rare variants by performing a comprehensive pedigree analysis would help establish better treatment strategies for life-threatening hereditary TAAD cases.

Primary ciliary dyskinesia (PCD) is a hereditary disease caused by genes related to motile cilia. We report two male pediatric cases of PCD caused by hemizygous pathogenic variants in the OFD1 centriole and centriolar satellite protein (OFD1) gene. The variants were NM_003611.3: c.[2789_2793delTAAAA] (p.[Ile930LysfsTer8]) in Case 1 and c.[2632_2635delGAAG] (p.[Glu878LysfsTer9]) in Case 2. Both cases had characteristic recurrent respiratory infections. Neither case had symptoms of oral-facial-digital syndrome type I. We identified a variant (c.2632_2635delGAAG) that has not been previously reported in any case of OFD1-PCD.

Dual-specificity tyrosine kinase 1A (DYRK1A) is a member of the CMGC family that is linked to a multitude of neuronal development pathways. Both overexpression and insufficiency of this gene are associated with many recognizable disorders, including Down syndrome and DYRK1A-related intellectual disability syndrome which is characterized by distinct physical features with microcephaly and global developmental delay. We report a case of DYRK1A-related intellectual disability syndrome caused by a novel mutation.

Discordance between the genetic sex and phenotype seen on ultrasound can identify disorders of sexual development (DSD) that previously escaped detection until puberty. We describe a 46, XY disorder of sexual differentiation caused by a rare mutation in the SF1 gene (OMIM]184757, (NR5A1). The mutation (NR5A1)-c.205C > G (p. Arg69Gly) was discovered after a phenotype-genotype discrepancy was encountered during prenatal care. The baby with 46, XY DSD has female external genitalia but evidence of Y chromosome-related regression of Müllerian structures and the absence of palpable gonads. We discussed the literature on phenotype-genotype discrepancy and the importance of care coordination between the antenatal and postnatal teams to ensure a timely diagnosis of DSD.

3-hydroxy isobutyl-CoA hydrolase (HIBCH) deficiency is a recently described, rare inborn error of valine metabolism associated with a Leigh syndrome-like phenotype, neurodegenerative symptoms, and caused by recessive mutations in the HIBCH gene. We report the most severe case to date of an intrauterine growth-restricted term male who presented with severe acidosis and a high anion gap soon after birth. The manifestation was fatal that led to death within 36 hours of life. The diagnosis was made postnatally by Whole Genome Sequencing (WGS). We report a rapid and fatal event of HIBCN in a neonate and review of the literature.

Multiple primary cancers (MPCs) are defined as the presence of more than one cancer in an individual that is not due to recurrence, metastasis, or local spread. Different factors such as copathogenic genetic mutations, environmental factors, lifestyle, and first cancer treatment increase the possible occurrence of subsequent malignancies. In recent years, the risk of MPCs has increased due to improved treatment; however, quadruple primary malignancies are still rare and require further investigation and treatment of the underlying cause. Here, we present a 64-year-old man with a 40-year history of cigarette smoking who developed quadruple primary malignancies of the epiglottis, kidney, pancreas, and lung. To investigate the possible genetic cause, we performed WES, and a variant of c.580G > A (Ala194Thr) was discovered in exon 5 of the Krebs cycle enzyme gene, fumarate hydratase (FH). This substitution was classified as VUS in Clinvar and likely pathogenic by Varsome and Franklin software. The structural analysis showed that the variation found was localized in a highly conserved alpha helix in the D2 domain near the FH hinge region (<6 Å), suggesting that enzyme activity was affected by a perturbation in protein quaternary structure. Because of the well-established role of FH mutations in renal cancer risk, it was possible that the FH mutation could have led to the development of renal cell carcinoma in this case. The biological mechanisms of MPCs suggest that subsequent primary malignancies are triggered by the combined effects of environmental factors, such as smoking and genetics.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem disabling disease with unclear etiology and pathophysiology, whose typical symptoms include prolonged debilitating recovery from fatigue or postexertional malaise (PEM). Disrupted production of adenosine triphosphate (ATP), the intracellular energy that fuels cellular activity, is a cause for fatigue. Here, we present a long-term case of ME/CFS: a 75-year-old Caucasian female patient, whose symptoms of ME/CFS were clearly triggered by an acute infection of the Epstein-Barr virus 24 years ago (mononucleosis). Before then, the patient was a healthy professional woman. A recent DNA sequence analysis identified missense variants of mitochondrial respiratory chain enzymes, including ATP6 (ChrMT: 8981A > G; Q152R) and Cox1 (ChrMT: 6268C > T; A122V). Protein subunits ATP6 and Cox1 are encoded by mitochondrial DNA outside of the nucleus: the Cox1 gene encodes subunit 1 of complex IV (CIV: cytochrome c oxidase) and the ATP6 gene encodes subunit A of complex V (CV: ATP synthase). CIV and CV are the last two of five essential enzymes that perform the mitochondrial electron transport respiratory chain reaction to generate ATP. Further analysis of the blood sample using transmission electron microscopy demonstrated abnormal, circulating, extracellular mitochondria. These results indicate that the patient had dysfunctional mitochondria, which may contribute directly to her major symptoms, including PEM and neurological and cognitive changes. Furthermore, the identified variants of ATP6 (ChrMT: 8981A > G; Q152R) and Cox1 (ChrMT: 6268C > T; A122V), functioning at a later stage of mitochondrial ATP production, may play a role in the abnormality of the patient's mitochondria and the development of her ME/CFS symptoms.