Case Reports in Genetics最新文献

Neonatal liver disease is a broad entity. When it presents in conjunction with other abnormalities, it raises the question of a potential underlying genetic cause. Etiologies that were once difficult to diagnose are becoming more readily identifiable with the arrival of next-generation sequencing. We present a rare cause of neonatal liver disease, a FOCAD gene variant, that was determined to be the most likely cause of an infant's liver disease and other findings. This case adds to only a few reports in the literature on this presentation in the neonatal period.

Achromatopsia (ACHM) (MIM: 262300) is an autosomal recessive disorder characterized by reduced visual acuity and color blindness. In this report, we review the case of a 14-year-old male patient diagnosed with achromatopsia with a history of retinal dystrophy, cone dysfunction with normal dark-adapted response on ERG, congenital nystagmus, farsightedness, and astigmatism. The diagnostic exome sequencing previously revealed a single maternally inherited pathogenic CNGB3 variant (c.1148delC, p.(T383lfs∗13). Following enrollment in the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine (IUSM), genome sequencing (GS) identified a second CNGB3 known variant c.1663-1205G > A p.(Gly555Leufs∗33), which was classified as likely pathogenic. Identification of this variant in the patient provided the evidence needed for a molecular diagnosis and ended a 15-year diagnostic odyssey for the patient and his family. With a diagnosis, the patient is eligible for gene therapy and qualifies for the state-run Vocational Rehabilitation Program and bioptic driving.

Nephronophthisis (NPHP) is a hereditary renal disorder characterized by the progression to end-stage renal disease (ESRD) at a young age. Our understanding of this disorder continues to improve as we identify more genes and gene variants associated with NPHP. In this report, we present a young patient with newly diagnosed advanced renal impairment and a strong family history of ESRD at a young age. The patient's kidney biopsy showed features suggestive of severe chronic interstitial nephritis, along with histopathological findings of advanced renal disease. Genetic testing revealed a novel variant in the IQCB1/NPHP5 gene, which is autosomal recessive. Family genetic analysis revealed that the patient's parents and two of his children are heterozygous for the identified variant, while two siblings with ESRD are homozygous for the IQCB1 p.(Ala486Asp) variant. Unlike previously described mutations in the IQCB1/NPHP5 gene, the patient and his affected siblings do not have retinitis pigmentosa. We report this novel gene variant in a Saudi family, describe its associated clinical features, and present the results of the family segregation analysis.

Dep domain-containing Protein 5 (DEPDC5), encoded by the gene DEPDC5, regulates the cell cycle by inhibiting the mTORC1 pathway in response to amino acid deficiency. Loss of function DEPDC5 variants are recognized to present as focal familial epilepsy; however, associations with comorbid brain malformations and neurodevelopmental disorders have also been reported. mTOR inhibitors were found to benefit DEPDC5-knockout mice. Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder caused by loss of function of FMR1, and females are expected to have milder neurodevelopmental presentations than males. The reported individual is a 17-year-old female diagnosed with FXS at 1 year of age, but the severity of her neuropsychiatric symptoms prompted further genetic testing at age 14, revealing a likely pathogenic c.4307_4310del DEPDC5 variant. Following this diagnosis, she was started on the mTOR inhibitor sirolimus without significant clinical response. She has never been diagnosed with epilepsy; however, her DEPDC5 and FXS dual diagnosis was thought explanatory for her presentation. A review of 213 previously reported individuals with DEPDC5-related disorder demonstrated that 15.2% of individuals do not have epilepsy, 24.3% have intellectual disability, and 33.8% have brain malformations. Her lack of response to sirolimus may represent the presence of a critical treatment window for mTOR inhibitors in neurodevelopmental disorders.

We present a case of an optic nerve coloboma in a 10-month-old girl found to have compound heterozygous USH2A variants. There were no other dysmorphic features or ocular developmental anomalies. To our knowledge, this is the first report in literature of a concomitant optic nerve coloboma in a case of nonsyndromic retinitis pigmentosa related to USH2A variants.

Background: Bartter syndrome is a rare genetic illness characterized by impairment in kidney function caused by different gene defects. The primary pathogenic mechanism of Bartter syndrome is defective salt reabsorption, predominantly in the thick ascending limb of the loop of Henle. Case Presentation: Here, we present a case series between 2 siblings diagnosed with Bartter syndrome through clinical and genetic analyses. Both patients presented with severe dehydration secondary to polyuria which caused persistent electrolyte imbalances. However, the second sibling presented with hydrocephalus which may be associated with Bartter Syndrome. Genetic analysis determined the presence of a known pathogenic mutation and a novel mutation in the CLCNKB variant. Conclusions: Bartter syndrome Type III is a genetic disorder that must be identified clinically without delay, as it typically manifests as acute dehydration due to polyuria and vomiting. Hydrocephalus, although cannot be concluded to be a complication of Bartter syndrome, can be associated due to several electrolyte imbalances involved in this condition. Genetic testing is essential for identifying unidentified pathogenic variants that will aid future patients diagnosed with this condition. Genetic counseling is of the utmost importance for these families affected by the condition in question.

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.