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 achromatop...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 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 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...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 /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 p.(Ala486Asp) variant. Unlike previously described mutations in the /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.
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...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.
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 pre...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.
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, predominant...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. 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. 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...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 (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 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 with homozygous C677T 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 percentile with above average verbal IQ (66 percentile), difficulties with quantitative reasoning, dyspraxia, below average visual-spatial skills (2 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 variati...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. analysis identified only two deleterious heterozygous mutations within an evolutionarily well-conserved region of the sarcomeric genes /cardiac actin (c.664G > A/p.Ala222Thr) and /titin (c.33250G > A/p.Glu11084Lys). Further pedigree analysis revealed the father of the index case to carry with the mutation. Surprisingly, the 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 mutation in in coexpression of a 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.
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder caused by heterozygous pathogenic variants and is characterized by both progressive heterotopic ossification of the soft tissues and congenital malfo...Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder caused by heterozygous 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. We report the case of a young boy with FOP who sustained multiple major fractures due to epileptic loss of consciousness. 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. This case expands our understanding of the phenotypic diversity of FOP and the functional versatility of -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, a...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 ( 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 heterozygous deletion at 13q12.3 in the proband, fully encompassing all coding exons of the gene yet not affecting any other neighboring genes. This case report presents a rare 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 . Our findings, together with previous reports, strongly support the pathogenic role of 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 results in the...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 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 : 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...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...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: (c.4819G > A, p.[Gly1607Ser]) and (c.365G > A, p.[Arg122His]). Familial cosegregation analysis revealed that the novel de novo variant was present only in the proband, and the variant was also found in his nonaffected mother, and thus the variant was classified as likely pathogenic. 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.
Xu Y, Tsurinaga Y, Matsumoto T
… +13 more, Muta R, Yano T, Sakaida H, Masuda S, Ueda K, Feng G, Gotoh S, Ogawa S, Ikejiri M, Nakatani K, Nagao M, Tanabe M, Takeuchi K
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 sa...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 () 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 -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 reco...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 differentia...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 gene (OMIM]184757, (). The mutation ()-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 mut...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, e...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 pos...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 (ChrMT: 8981A > G; Q152R) and (ChrMT: 6268C > T; A122V). Protein subunits ATP6 and Cox1 are encoded by mitochondrial DNA outside of the nucleus: the gene encodes subunit 1 of complex IV (CIV: cytochrome c oxidase) and the 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.
Hyperphosphatasia with mental disorder (HPMRS) is a rare autosomal recessive disease caused by gene mutations in enzymes involved in the synthesis and remodeling of lipids. Seven-month-old boy diagnosed with bilateral gl...Hyperphosphatasia with mental disorder (HPMRS) is a rare autosomal recessive disease caused by gene mutations in enzymes involved in the synthesis and remodeling of lipids. Seven-month-old boy diagnosed with bilateral glaucoma had a cleft palate, facial dysmorphism, hypertelorism, a broad nasal bridge, and large fleshy earlobes. A brain MRI scan also revealed brain abnormalities. The observed phenotype in a seven-month-old boy is in agreement with the phenotypic features of HPRMS type-4. Whole exome sequencing revealed a possible pathogenic variant of in a homozygous state (c.320C > T, p.Ser107Leu) which supported the diagnosis of HPRMS type-4. We report an unusual presentation for HPMRS and suggest adding this syndrome to the list of differential diagnoses of syndromic congenital glaucoma.
Chromothripsis is characterized by shattering and subsequent reassembly of chromosomes by DNA repair processes, which can give rise to a variety of congenital abnormalities and cancer. Constitutional chromothripsis is a...Chromothripsis is characterized by shattering and subsequent reassembly of chromosomes by DNA repair processes, which can give rise to a variety of congenital abnormalities and cancer. Constitutional chromothripsis is a rare occurrence, reported in children presenting with a wide range of birth defects. We present a case of a female child born with multiple major congenital abnormalities including severe microcephaly, ocular dysgenesis, heart defect, and imperforate anus. Chromosomal microarray and mate pair sequencing identified a complex chromosomal rearrangement involving the terminal end of the long arm of chromosome 2, with two duplications (located at 2p25.3-p25.1 and 2q35-q37.2 regions) and two deletions (located at 2q37.2-q37.3 and 2q37.3 regions) along with structural changes including inverted segments. A review of the literature for complex rearrangements on chromosome 2 revealed overlapping features; however, our patient had a significantly more severe phenotype which resulted in early death at the age of 2 years. Breakpoints analysis did not reveal the involvement of any candidate genes. We concluded that the complexity of the genomic rearrangement and the combined dosage/structural effect of these copy number variants are likely explanations for the severe presentation in our patient.