Case Reports in Genetics最新文献

Fragile X syndrome (FXS) presents with autism spectrum disorder (ASD), intellectual disability, developmental delay, seizures, hypotonia during infancy, joint laxity, behavioral issues, and characteristic facial features. The predominant mechanism is due to CGG trinucleotide repeat expansion of more than 200 repeats in the 5'UTR (untranslated region) of FMR1 (Fragile X Messenger Ribonucleoprotein 1) causing promoter methylation and transcriptional silencing. However, not all patients presenting with the characteristic phenotype and point/frameshift mutations with deletions in FMR1 have been described in the literature. It is believed that < 1% of cases are caused by point mutations. Genetic and functional testing of point mutations in FXS has yielded insights on KH domain RNA-binding properties of FMRP (Fragile X Messenger Ribonucleoprotein Protein) and nuclear export of the protein. Here, we report a c.1599_1601del p.Arg534del novel mutation in FMR1 with homozygous C677T MTHFR polymorphism in a 12-year-old boy. He presents with unique phenotype of FXS with ASD, developmental delay, nonverbal learning disorder (NVLD), overall IQ in the 5^th percentile with above average verbal IQ (66^th percentile), difficulties with quantitative reasoning, dyspraxia, below average visual-spatial skills (2^nd percentile), difficulty with social pragmatics and social understanding, and executive dysfunction. He has a strong aptitude for music and exceptional aural skills. Identification of novel variants has helped in understanding functional aspects of FMRP. In addition, it aids families in genetic counseling and in administering therapies for children with FXS who present with atypical features.

Structural or electrophysiologic cardiac anomalies may compromise cardiac function, leading to sudden cardiac death (SCD). Genetic screening of families with severe cardiomyopathies underlines the role of genetic variations in cardiac-specific genes. The present study details the clinical and genetic characterization of a malignant dilated cardiomyopathy (DCM) case in a 1-year-old Mexican child who presented a severe left ventricular dilation and dysfunction that led to SCD. A total of 132 genes (48 structure- and 84 electrical-related genes) were examined by next generation sequencing to identify potential causative mutations in comparison to control population. In silico analysis identified only two deleterious heterozygous mutations within an evolutionarily well-conserved region of the sarcomeric genes ACTC1/cardiac actin (c.664G > A/p.Ala222Thr) and TTN/titin (c.33250G > A/p.Glu11084Lys). Further pedigree analysis revealed the father of the index case to carry with the TTN mutation. Surprisingly, the ACTC1 mutation was not harbored by any first-degree family member. Computational 3D modeling of the mutated proteins showed electrostatic and conformational shifts of cardiac actin compared to wild-type version, as well as changes in the stability of the compact/folded states of titin that normally contributes to avoid mechanic damage. In conclusion, our findings suggest a likely pathogenic de novo mutation in ACTC1 in coexpression of a TTN variant as possible causes of an early onset of a severe DCM and premature death. These results may increase the known clinical pathogenic variations that may critically alter the structure of the heart, whose fatality could be prevented when rapidly detected.

Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder caused by heterozygous ACVR1 pathogenic variants and is characterized by both progressive heterotopic ossification of the soft tissues and congenital malformations of the great toe. In addition to pathological skeletal metamorphosis, patients with FOP experience diverse neurological symptoms such as chronic pain and involuntary movements; however, little is known about the association between FOP and epileptic seizures. Methods: We report the case of a young boy with FOP who sustained multiple major fractures due to epileptic loss of consciousness. Results: Based on generalized electroencephalographic abnormalities and the presence of myoclonic movements, the patient was diagnosed with juvenile myoclonic epilepsy. The absence of seizures was well-controlled with valproic acid, whereas occasional abrupt myoclonic movements of the hands and feet persisted. Conclusion: This case expands our understanding of the phenotypic diversity of FOP and the functional versatility of ACVR1-mediated bone morphogenetic protein (BMP) signaling.

Heterozygous microdeletions at 13q12.3 are associated with a rare genetic disorder, 13q12.3 microdeletion syndrome, characterized by intellectual disability, microcephaly, development delay, facial dysmorphisms, atopy, and obesity. Reported 13q12.3 microdeletions vary in size and typically encompass multiple genes. Previous studies have defined a minimal overlap region of 13q12.3 microdeletions and suggested that most of the phenotype associated with the 13q12.3 microdeletion syndrome could be attributed to the loss of the high mobility group box 1 (HMGB1) gene within the overlap region. Here, we report a pediatric patient who had typical phenotypic features of 13q12.3 microdeletion syndrome, including motor and moderate speech developmental delays, microcephaly, and severe atopy, along with anxiety and aggressive behaviors. Trio-based microarray analysis identified a 62-kb apparently de novo heterozygous deletion at 13q12.3 in the proband, fully encompassing all coding exons of the HMGB1 gene yet not affecting any other neighboring genes. This case report presents a rare HMGB1 single-gene deletion in a patient with classic features of 13q12.3 microdeletion syndrome, allowing a better delineation of clinical phenotypes associated with the loss of HMGB1. Our findings, together with previous reports, strongly support the pathogenic role of HMGB1 haploinsufficiency in the 13q12.3 microdeletion syndrome.

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.