Dilated cardiomyopathy with ataxia syndrome is a rare mitochondrial disease caused by autosomal recessive mutations in the gene. The disease has been described in detail in the Canadian Hutterite population, but a few s...Dilated cardiomyopathy with ataxia syndrome is a rare mitochondrial disease caused by autosomal recessive mutations in the gene. The disease has been described in detail in the Canadian Hutterite population, but a few sporadic cases with de novo mutations have been published worldwide. We describe a homozygous pathogenic variant in the gene, diagnosed in Northern Greece, presenting with genital anomalies, growth failure, cardiomyopathy, and ataxia, but without increased urinary 3-methylglutaconic acid and additional presence of vitamin D disorders, hypercalciuria, and osteopenia. This case not only expands the clinical characteristics of 3-methylglutaconic aciduria type V (MGCA5) but also highlights the power of genetic analysis for detecting a diagnosis when the metabolic screen is negative.
Microrchidia CW-type zinc finger protein 2 (MORC2) is an ATPase-containing nuclear protein which regulates transcription through chromatin remodelling and epigenetic silencing. may have a role in the development of neur...Microrchidia CW-type zinc finger protein 2 (MORC2) is an ATPase-containing nuclear protein which regulates transcription through chromatin remodelling and epigenetic silencing. may have a role in the development of neurones, and dominant variants in this gene have recently been linked with disorders including Charcot-Marie-Tooth type 2Z disease, spinal muscular atrophy and, more recently, a neurodevelopmental syndrome consisting of developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (DIGFAN), presenting with hypotonia, microcephaly, brain atrophy, intellectual disability, hearing loss, faltering growth, and craniofacial dysmorphism. Notably, variants in have shown clinical features overlapping with those of Cockayne and Leigh syndromes. Here, we report a case of -related DIGFAN syndrome in a female infant caused by a novel heterozygous variant. The condition was early onset and severe, further expanding the range of genotypes associated with this disorder. Clinical features included unilateral hearing loss, developmental delay and regression within the first year of life, microcephaly, severe feeding difficulties, and faltering growth, resulting in death at 13 months of age.
Genetic variants in are the most common cause of hereditary spastic paraplegia (HSP), entitled spastic paraplegia type 4 (SPG4). Inheritance is autosomal dominant, and age of onset can vary from childhood to adulthood....Genetic variants in are the most common cause of hereditary spastic paraplegia (HSP), entitled spastic paraplegia type 4 (SPG4). Inheritance is autosomal dominant, and age of onset can vary from childhood to adulthood. Pathogenic variants are often observed in isolated cases, likely due to reduced penetrance and clinical variability. We report an isolated case of SPG4 associated with a novel likely pathogenic variant in . A 38-year-old woman presented with an eight-year history of progressive difficulty walking. Neurological examination revealed spastic paraparesis in the absence of upper motor neuron dysfunction, sensory deficits, or intellectual disability. Magnetic resonance imaging (MRI) of the brain and spinal cord was normal. No family members had similar complaints. Genetic analysis revealed a novel heterozygous sequence variant in , c.1751A > G p.(Asp584Gly) (NM_014946.4). The affected amino acid is highly conserved among orthologue and paralogue species. Four other nucleotide substitutions predicted to affect the same amino acid, a "hot spot", have been reported previously in adult-onset HSP. This report describes a novel variant in a female with HSP without a known family history of the disorder.
Structural chromosomal aberrations like translocations have been shown to cause spermatogenic failure. We report a rare 46,X,t(Y;10)(q12;p14) balanced translocation in an otherwise healthy non-obstructive azoospermic mal...Structural chromosomal aberrations like translocations have been shown to cause spermatogenic failure. We report a rare 46,X,t(Y;10)(q12;p14) balanced translocation in an otherwise healthy non-obstructive azoospermic male with high follicle-stimulating hormone (26.65 IU/L) and high luteinizing hormone (13.58 IU/L). The patient was referred to us after clinical, hormonal, and histopathological investigations to identify chromosomal abnormalities by karyotyping and fluorescence in situ hybridization (FISH). Analysis of the banding pattern by karyotyping followed by FISH confirmed reciprocal translocation and identified the breakpoints at Yq heterochromatin (Yq12) and 10p14. Further molecular tests including AZF microdeletion assay were done, and the results, which showed no mutations in the analyzed genes, were provided by the referring doctor. Thus, our study points to the importance of conventional cytogenetic techniques in the preliminary evaluation of a genetic abnormality in cases of infertility and would help the patient make an informed decision before pursuing assisted reproductive technology.
Concurrent microduplication and microdeletion of the chromosome 22q11.2 region are a rarely reported phenomenon. We describe a case of germline 22q11.21 microduplication syndrome with concurrent mosaic 22q11.2 deletion i...Concurrent microduplication and microdeletion of the chromosome 22q11.2 region are a rarely reported phenomenon. We describe a case of germline 22q11.21 microduplication syndrome with concurrent mosaic 22q11.2 deletion in a pregnant patient, identified by chromosomal microarray and FISH after noninvasive prenatal genetic screening (cfDNA) results discordant with family history. The patient was referred to maternal-fetal medicine (MFM) at 14 weeks' gestation secondary to an SNP-based cfDNA result of a suspected maternal 22q11.2 deletion and a fetal risk of 1 in 2 for 22q11.2 deletion syndrome. The patient reported a similar cfDNA result in a previous pregnancy; however postnatal chromosomal microarray on that child identified an atypical 22q11.21 microduplication. We report the maternal chromosomal microarray findings of a germline 726 kb 22q11.21 duplication and a mosaic 1.33 Mb 22q11.2 deletion and highlight the copy number variant data generated by cfDNA in this unique case. This family adds to the limited literature of concurrent 22q11.2 microduplication and microdeletion carriers.
Bromodomain and PHD finger containing 1 ()-related neurodevelopmental disorder is characterized by intellectual disability, developmental delay, hypotonia, dysmorphic facial features, ptosis, and blepharophimosis. Both...Bromodomain and PHD finger containing 1 ()-related neurodevelopmental disorder is characterized by intellectual disability, developmental delay, hypotonia, dysmorphic facial features, ptosis, and blepharophimosis. Both and inherited pathogenic variants have been previously reported in association with this disorder. We report two affected female siblings with a novel variant in c.2420_2433del (p.Q807Lfs27) identified through whole-exome sequencing. Their history of mild intellectual disability, speech delay, attention deficient hyperactivity disorder (ADHD), and ptosis align with the features previously reported in the literature. The absence of the variant in parental buccal samples provides evidence of a frameshift pathogenic variant, most likely as a result of parental gonadal mosaicism, which has not been previously reported. The frameshift pathogenic variant reported here lends further support to haploinsufficiency as the underlying mechanism of disease. We review the literature, compare the clinical features seen in our patients with others reported, and explore the possibility of genotype-phenotype correlation based on the location of pathogenic variants in . Our study helps to summarize available knowledge and report the first case of a frameshift pathogenic variant in in two siblings with this neurodevelopmental disorder.
INTRODUCTION: There is evidence that neurodevelopmental disorders are associated with chromosomal abnormalities. Current genetic testing can clinch an exact diagnosis in 20-25% of such cases. A 3 years and 11 months old...INTRODUCTION: There is evidence that neurodevelopmental disorders are associated with chromosomal abnormalities. Current genetic testing can clinch an exact diagnosis in 20-25% of such cases. A 3 years and 11 months old boy with global developmental delay had repetitive behaviors and hyperkinetic movements. He was stunted and underweight. He had ataxia, limb dyskinesia, triangular face, microcephaly, upward slanting palpebral fissure, hypertelorism, retrognathia, posteriorly rotated ears, long philtrum, thin lips, broad nasal tip, polydactyly, tappering fingers, and decreased tone in the upper and lower limbs with normal deep tendon reflexes. Magnetic resonance imaging of the brain, ultrasound of the abdomen, and ophthalmological evaluation were normal. Brain evoked response auditory revealed bilateral moderate hearing loss. He fulfilled the Diagnostic Statistical Manual 5 criteria for autism. In the Vineland Social Maturity Scale, his score indicated a severe delay in social functioning. His genetic evaluation included karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray analysis (CMA). The karyotype report from high-resolution lymphocyte cultures was mos 46, XY, der(3)t(3; 5)(p26; p15.3)[50]/46, XY,der(5) t(3;5) (p26;p15.3)[50].ish. His karyotype report showed a very rare and abnormal mosaic pattern with two cell lines (50% each). Cell-line#1: 3pter deletion with 5pter duplication (3pter-/5pter+) and cell-line#2: 3pter duplication with 5pter deletion (3pter+/5pter-) derived from a reciprocal translocation t(3; 5)(p26; p15.3) which was confirmed by FISH. The chromosomal microarray analysis report was normal. The two cell lines (50% each) seem to have balanced out at the whole genome level. Occupational, sensory integration, and behavior modification therapy were initiated for his autistic features, and anticholinergic trihexiphenidyl was prescribed for hyperkinetic movements. CONCLUSION: This case highlights a rare genetic finding and the need for timely genetic testing in a child with dysmorphism and autism with movement disorder to enable appropriate management and genetic counselling.
The gene encodes megalin (LRP-2/GP330), a large single-spanning transmembrane glycoprotein that serves as a multiligand endocytotic receptor and mediates the reabsorption of albumin in the proximal renal tubule. is imp...The gene encodes megalin (LRP-2/GP330), a large single-spanning transmembrane glycoprotein that serves as a multiligand endocytotic receptor and mediates the reabsorption of albumin in the proximal renal tubule. is implicated in an autosomal recessive disorder characterized by dimorphisms, ocular anomalies, sensorineural deafness, proteinuria, epilepsy, and intellectual disability: a clinical condition called Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR) syndrome. Pathogenic variants in have been reported in fewer than 60 patients, but a detailed description of seizures, electroencephalographic patterns, imaging findings, behavioral phenotype, and long-term follow-up is still needed. We provide a clinical report of two mono-chorionic twins with -related disease manifesting developmental delay, autistic features, seizures, proteinuria, and sleep disorders. By sequencing clinical exome, candidate rare variants, c.6815G > A, p. (Arg2272His), inherited from the mother and c.12725A > G, p. (Asp4242Gly), inherited from the father, were identified. During follow-up, at the age of 7, the main clinical features of the patients included insomnia, autistic features, severe psychomotor delay, and absent speech. The patients were under treatment with risperidone, antiseizure medications (ASMs), and supplementation of alpha-lactalbumin for self-injury and sleep disturbance. Our study confirmed the wide spectrum of behavioral and neurological and psychiatric features of this rare condition, suggesting new treatment options.
Loss of expression of paternally imprinted genes in the 15q11.2-q13 chromosomal region leads to the neurodevelopmental disorder Prader-Willi Syndrome (PWS). The PWS critical region contains four paternally expressed prot...Loss of expression of paternally imprinted genes in the 15q11.2-q13 chromosomal region leads to the neurodevelopmental disorder Prader-Willi Syndrome (PWS). The PWS critical region contains four paternally expressed protein-coding genes along with small nucleolar RNA (snoRNA) genes under the control of the promoter, including the snoRNA gene cluster that is implicated in the PWS disease etiology. A 5-7 Mb deletion, maternal uniparental disomy, or an imprinting defect of chromosome 15q affect multiple genes in the PWS critical region, causing PWS. However, the individual contributions of these genes to the PWS phenotype remain elusive. Reports of smaller, atypical deletions may refine the boundaries of the PWS critical region or suggest additional disease-causing mechanisms. We describe an adult female with a classic PWS phenotype due to a 78 kb microdeletion that includes only exons 2 and 3 of with apparently preserved expression of .
. Monogenic mutations as the cause of recurrent ischemic cerebral small-vessel disease with leukodystrophy are rare. COL4A1 gene mutations are a relatively new etiology of cerebrovascular lesions in young adults; however.... Monogenic mutations as the cause of recurrent ischemic cerebral small-vessel disease with leukodystrophy are rare. COL4A1 gene mutations are a relatively new etiology of cerebrovascular lesions in young adults; however, any patient has been reported from Latin America. . We presented a Mexican young female with leukodystrophy and recurrent stroke secondary to COL4A1 monogenic mutation. . COL4A1 monogenic mutations are associated with cerebral small-vessel disease and other systemic manifestations. To date, there is little evidence to justify the treatment and prevention of recurrent strokes in patients with this mutation.
Up to now, more than 300 pathogenic variants have been identified in the -globin gene, some of which are categorized as silent mutations that do not change the hematological indices. In the present study, our aim is to i...Up to now, more than 300 pathogenic variants have been identified in the -globin gene, some of which are categorized as silent mutations that do not change the hematological indices. In the present study, our aim is to introduce the first report of a case with thalassemia intermedia with coinheritance of the c.315 + 1 G > A pathogenic variant and a silent variant (HBB: c.-19 G > C) that was missed during the screening program. Multiplex-Gap-PCR and Sanger sequencing methods were applied to identify and -globin gene mutations in a 26-year-old male subject with diagnosis of thalassemia. The identified mutations were also checked on the parent's sample. The CBC and capillary electrophoresis tests were performed on the parent's blood samples. The case was compound heterozygote for the c.315 + 1 G > A and c.-19 G > C (rs1239893012) variants. The subject's mother carried the c.-19 G > C variant in the -globin gene while her CBC and electrophoresis test results showed a normal pattern. Silent mutations are susceptible to being missed during premarital screening of -thalassemia carriers, and the c.-19 G > C variant is recommended to be classified as a pathogenic variant in the -globin gene.
Arthrogryposis multiplex congenita (AMC) is characterized by nonprogressive symmetric contractures of multiple joints with normal intellect and normal systemic examination. AMC is often due to fetal akinesia, which has n...Arthrogryposis multiplex congenita (AMC) is characterized by nonprogressive symmetric contractures of multiple joints with normal intellect and normal systemic examination. AMC is often due to fetal akinesia, which has neurologic, muscular, and connective tissue etiologies. We present a case of AMC due to a variant in the titin (TTN) gene in a term neonate. The infant is homozygous for this variant, , which is predicted to result in a truncated protein (∗). A literature search (PubMed) failed to find reports of this TTN variant. The variant was classified as pathogenic and submitted to ClinVar. Titin is the body's largest protein, expressed in skeletal and cardiac muscles and encoded by the TTN gene. Due to its large size (364 exons), the TTN gene has been difficult to sequence; the number of variants in the TTN gene and the spectrum of titinopathies are probably underestimated.
Cyclin-dependent kinase 13 () is a member of the cyclin-dependent serine/threonine protein kinase family. Members of this family are well known for their essential roles as master switches in cell cycle control. CDK13-re...Cyclin-dependent kinase 13 () is a member of the cyclin-dependent serine/threonine protein kinase family. Members of this family are well known for their essential roles as master switches in cell cycle control. CDK13-related disorder is a newly described genetic condition with characteristic clinical features including mild to severe intellectual disability, developmental delay, neonatal hypotonia, a variety of facial dysmorphism, behavioral problems, congenital heart defects, and structural brain abnormalities. We report a case of prenatal diagnosis of CDK13-related disorder. Detection of cystic hygroma with thickened nuchal fold led to prenatal genetic investigation, which identified a novel likely pathogenic variant in the gene (c.900C > G, p.Tyr300). Pregnancy was terminated and autopsy was performed. To our best knowledge, this is the first reported case of prenatal presentation of this condition with a detailed phenotypic description of the affected fetus.
The female characters with a 46, XY karyotype, historically termed Swyer syndrome, are commonly divided into complete and partial gonadal dysgenesis. The former is completely made up of the 46, XY chromosome, while the l...The female characters with a 46, XY karyotype, historically termed Swyer syndrome, are commonly divided into complete and partial gonadal dysgenesis. The former is completely made up of the 46, XY chromosome, while the latter results from 45, X/46, XY mosaicism. Both of them are sex chromosome disorders and are typically characterized by delayed puberty and primary amenorrhea due to disruption of the embryonic gonads into testes. In this report, we described a young female with mos 45, X [2]/46, X, psu idic (Y) (q11.2) [48] by karyotyping. Further copy number variation sequencing (CNV-seq) and fluorescent in situ hybridization (FISH) verified her chromosome alteration. The following gonadectomy and hormone replacement therapy were carried out, and the menstrual cycle recovered along with the development of bilateral breasts and uteruses. Herein, we aim to provide clinical management strategies for the patient with Swyer syndrome in clinical practice.
Despite increased prenatal and postnatal use of array comparative genomic hybridization (aCGH), isolated 8p23.1 duplication remains rare and has been associated with a widely variable phenotype. Here, we report an isolat...Despite increased prenatal and postnatal use of array comparative genomic hybridization (aCGH), isolated 8p23.1 duplication remains rare and has been associated with a widely variable phenotype. Here, we report an isolated 8p23.1 duplication in a fetus with an omphalocele and encephalocele that were incompatible with life. Prenatal aCGH demonstrated a 3.75 Mb de novo duplication of 8p23.1. This region encompassed 54 genes, 21 of which are described in OMIM, including and The summarized case demonstrates phenotypic features not previously described in 8p23.1 duplication syndrome and is reported in order to enhance understanding of the phenotypic variation.
We describe a 38-year-old male patient with intellectual disability and progressive motor symptoms who lacked an etiological diagnosis for many years. Finally, clinical exome sequencing showed a likely pathogenic variant...We describe a 38-year-old male patient with intellectual disability and progressive motor symptoms who lacked an etiological diagnosis for many years. Finally, clinical exome sequencing showed a likely pathogenic variant of the gene suggesting Partington syndrome. His main symptoms were mild intellectual disability, severe kinetic apraxia, resting and action tremor, dysarthria, tonic pupils, constant dystonia of one upper limb, and focal dystonia in different parts of the body, axial rigidity, spasticity, epilepsy, and poor sleep. Another likely pathogenic gene variant was observed in the gene and is in accordance with the observed early cardiomyopathy. Single-photon emission computed tomography imaging of dopamine transporters showed a reduced signal in the basal ganglia consistent with Parkinson's disease. Therapies with a variable number of drugs, including antiparkinsonian medications, have yielded poor responses. Our case report extends the picture of the adult phenotype of Partington syndrome.
We encountered a case with congenital iris coloboma, omphalocele, and developmental delay with a 2.5 Mb deletion on chromosome 4q25 encompassing , leading to Axenfeld-Rieger syndrome (ARS), and . ARS is characterized by...We encountered a case with congenital iris coloboma, omphalocele, and developmental delay with a 2.5 Mb deletion on chromosome 4q25 encompassing , leading to Axenfeld-Rieger syndrome (ARS), and . ARS is characterized by the aplasia of the anterior eye, odontogenesis, and abdominal wall aplasia. In our case, iris coloboma and omphalocele were thought to be caused by haploinsufficiency. However, these symptoms are nonspecific, and clinical symptoms alone can make it difficult to make a correct diagnosis. In addition, the genes responsible for developmental delay, among others, are not well understood. Developmental delay, in this case, might be caused due to haploinsufficiency. In spite of the partial deletion of , the causative gene of long QT syndrome type 4, the electrocardiogram was normal. Genetic testing can lead to a correct diagnosis, and it may be effective in detecting complications.
We present a case of a 4-year-old female with a de novo heterozygous variant in the ATN1 gene. The whole exome sequencing was performed on the patient and her parents, and a likely pathogenic, de novo variant was identif...We present a case of a 4-year-old female with a de novo heterozygous variant in the ATN1 gene. The whole exome sequencing was performed on the patient and her parents, and a likely pathogenic, de novo variant was identified in exon 5 of the ATN1 gene. There are two well-documented conditions associated with the ATN1 gene: congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA) syndrome and dentatorubral-pallidoluysian atrophy (DRPLA). Unlike DRPLA which is caused by an expanded trinucleotide repeat, CHEDDA syndrome is caused by variants in the histidine-rich (HX) motif at exon 7 of ATN1 similar to the de novo variant found in exon 5 of the presented individual. CHEDDA syndrome is a neurodevelopmental disorder previously documented in over 17 unrelated individuals. Compared to other documented CHEDDA syndrome cases, this individual shares similarities in respect to hypotonia, hearing impairment, impaired gross and fine motor ability, gastrointestinal abnormalities, hyperextensible joints, and frontal bossing. However, the individual presented here has only a moderate developmental delay and has acquired more developmental milestones such as higher-level language skills and more developed fine motor skills, than previously described individuals. The authors of this paper believe the patient's milder phenotype may be due to the variant's location outside of the canonic HX motif.
BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants of the gene. Heterozygous female patients may show much more variability in clinical manifestations, ranging from as...BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants of the gene. Heterozygous female patients may show much more variability in clinical manifestations, ranging from asymptomatic to full-blown disease. Because of this heterogeneous clinical picture in women, the diagnosis of FD has typically been delayed for more than a decade, and the optimal time to initiate treatment remains controversial. . Here, we present two unrelated female patients diagnosed with FD harbouring the same pathogenic variant. We discuss the implications of initiating specific therapy at different stages of the disease, with and without organ involvement (early versus late therapeutic intervention). CONCLUSIONS: These clinical cases suggest that initiating specific treatment at an earlier age in women with FD may prevent organ involvement and associated clinical events.
Autosomal recessive intellectual developmental disorder type 5 (MRT5, OMIM # 611091) is caused by biallelic pathogenic variants, leading to loss of function of the NSUN2 gene which encodes a methyltransferase involved in...Autosomal recessive intellectual developmental disorder type 5 (MRT5, OMIM # 611091) is caused by biallelic pathogenic variants, leading to loss of function of the NSUN2 gene which encodes a methyltransferase involved in several biological processes, ranging from stress response to neurodevelopment (Hussain 2021). The current literature shows that MRT5 typically manifests with intellectual disability, facial dysmorphism, juvenile cataracts, chronic nephritis, hearing impairment, seizures, cerebellar atrophy, and microcephaly (Pingree et al. 2021). We describe a case of a patient with MRT5 who developed epilepsy in his teens, a rare clinical presentation that has not yet been discussed at length in the literature. Our patient is a 15-year-old male with a history of autism, developmental delay, and focal epilepsy who underwent genetic testing and was found to have a homozygous frameshift mutation in NSUN2 predicted to cause loss of function. This case emphasizes that epilepsy can be a phenotypic manifestation in patients with MRT5.