Molecular Syndromology最新文献

Introduction: TUBGCP6-related disorder is a known cause of autosomal recessive microcephaly and chorioretinopathy, which was originally recognized as a new syndrome based on unique ocular findings on a phenotypic overlap of microcephalic primordial short stature. Since the elucidation of its molecular mechanism, limited families have been published in literature and the disorder remains rare worldwide.

Case presentation: We present the first Indian family with an affected child and sibling fetus with microcephaly, dysmorphism, and agyria/pachygyria complex on brain imaging in both and short stature, intellectual disability, and visual impairment in proband. As for many patients with long diagnostic odysseys, this child also underwent multiple genomic tests. Genome sequencing through the Indian Undiagnosed Disease Program (I-UDP) confirmed the diagnosis in both proband and sibling fetus. Compound heterozygous variants were identified in TUBGCP6 including an eleven base pair deletion (inherited from father) and 405 base pair large deletion (inherited from mother). Reverse phenotyping to confirm the ocular phenotype in proband confirmed TUBGCP6-related microcephaly and chorioretinopathy. We report third trimester microcephaly with ventriculomegaly and abnormal sulcation as part of the antenatal presentation for this condition.

Conclusion: This case represents an Indian family with a seemingly obvious clinical diagnosis compounded by a long diagnostic odyssey and the first ever structural variant to be identified via whole genome sequencing in TUBGCP6 in trans with an indel variant.

Introduction: Pontocerebellar hypoplasia (PCH) represents a group of rare disorders with prenatal onset and time-dependent loss of brain parenchyma, predominantly affecting the cerebellum and pons with variable involvement of supratentorial structures. Radiologically and pathologically, they are characterized by small cerebellum and pons. Our study aimed to screen for the TSEN54 gene variants in Egyptian patients with PCH for proper counseling and to describe the brain MRI and the clinical phenotype and compare, them to those described in the literature.

Methods: Thirty patients from thirty Egyptian families with a diagnosis of PCH based on neuroimaging findings were selected. Clinical evaluation, radiological findings, and genetic investigations were done for all patients.

Results: The common missense variant c.919G>T (p.A307S) was identified in only 6 patients from six unrelated families (6/30; 20%) who showed different degrees of pontocerebellar malformations on brain imaging.

Conclusion: The presence of a dragonfly/butterfly-like pattern in the coronal section of the cerebellum recommends genetic testing of TSEN54 as a first step. For negative cases, whole-exome sequencing is essential to reach a definite diagnosis and determine the etiology.

Introduction: Partial 17q duplication is a rare chromosome abnormality. Features include severe psychomotor retardation, intellectual disability, facial dysmorphism, proximal limb shortness, and hyperlaxity of limb joints.

Case presentation: The proband is a 7-year and 4-month-old boy with developmental delay, facial abnormality, joint laxity and scoliosis, ventriculomegaly, hydrocephalus, hypophosphatemia, and squint, while his older brother is a fetus who was aborted at 33rd week of gestation because of multiple malformations including ventriculomegaly and moderate hydrocephalus. Both siblings have features such as ventriculomegaly and hydrocephalus.

Conclusion: Here, we report 2 sibling cases with 17q25 duplication from a maternal translocation t(14;17). Our findings expanded the clinical spectra and described the fetal phenotype of 17q25 microduplication.

[This corrects the article DOI: 10.1159/000539115.].

Introduction: Autism spectrum disorders (ASDs) are complex neurodevelopmental disorders characterized by restrictive repetitive behavior and impairment in social and communication skills. They are extremely heterogeneous with a strong genetic preponderance. They are clinically highly convoluted, presenting with multiple comorbid conditions and syndromic features. More than 100 genes have been identified to date.

Method: Whole exome sequencing (WES) has emerged as a valuable tool in evaluating the genetic underpinnings of ASDs, be it the syndromic or the idiopathic variants. In the current study, we performed WES on a multiplex family of Indian origin to investigate the disease etiology in the siblings (S1 [Female] and S2 [Male]) exhibiting ASD syndromic features, at both clinical and genetic aspects.

Results: Exome sequencing identified a missense variant (NM_030665.4:c.5320C>T; p.Arg1774Trp) in S1 resulting in RAI1 haploinsufficiency. Validation by Sanger sequencing confirmed that the variant was true positive and maternally transmitted in the subject. Likewise, we report an inherited missense variant at the same locus (17p11.2) corresponding to the FLII gene (NM_002018.4:c.2030A>C; p.Glu677Ala) in the other sibling, S2. Both the variants were reported in the Smith Magenis syndrome (SMS) critical region justifying their contribution to the presentation of the syndromic SMS features. These WES findings were consistent with the clinical findings that imply SMS features in both siblings.

Conclusion: The current study employed WES to provide insights into the genetic complexity associated with syndromic ASD and how that contributes to the disease heterogeneity. Moving forward, combinatorial approaches and findings from syndromic ASDs can potentially act as indicators to understand the genetic and phenotypic variations seen in idiopathic ASD.

Background: MOMO syndrome is a rare disorder with variable presentation and unknown etiology belonging to the overgrowth syndromes group.

Case presentation: The authors describe a patient presenting with severe developmental delay, absent speech, autism spectrum disorder, central nervous system malformations, bilateral optic atrophy, and postnatal overgrowth, besides a dysmorphic and progressive coarse face. A clinical diagnosis of MOMO syndrome was proposed, but he developed megaesophagus, megacolon, paraparesis, and severe acne during the clinical follow-up, which are not described in this condition. Whole-genome sequencing detected a deletion of 11.9 Mb at 3q13.2q21.2 comprising 80 genes, including the ZBTB20 gene associated with Primrose syndrome.

Conclusion: Despite the atypical manifestations in this patient, the overlapping features between MOMO syndrome, Primrose syndrome, and 3q13.31 deletion led the authors to propose that MOMO syndrome could be part of the Primrose/3q13.31 microdeletion syndrome spectrum.

Introduction: Mitochondrial DNA depletion syndromes (MDDSs) are a group of clinically and genetically heterogeneous disorders. In the present study, we aimed to investigate the frequency of MDDS in children under the age of 5 years with suspected mitochondrial hepatopathy and to evaluate this group of patients using MDDS gene panel and clinical exome sequencing (CES) genetic analysis methods.

Methods: Patients under 5 years of age who were clinically suspected to have mitochondrial hepatopathy and had neonatal acute liver failure, hepatic steatohepatitis, cholestasis, or cirrhosis with chronic liver failure of insidious onset were included.

Results: Forty patients (20 female, 50%) were enrolled, with a median age of 102 [57-263.8] days. Icteric appearance was identified in 28 (70%) of the patients, hepatomegaly in 27 (67.5%), splenomegaly in 10 (25.0%), and hypotonicity in 10 (25.0%); moreover, elevated international normalized ratio was detected in 77.5%, cholestasis in 77.5%, and elevated lactate levels in 62.5%. Molecular genetic diagnosis was made in 9 patients (22.5%) with the MDDS gene panel and in 17 (42.5%) patients with the CES analysis. All patients diagnosed with MDDS had a history of parental consanguinity, while the rate in those without MDDS was 54.8% (p = 0.012). High lactate levels were identified in all those with MDDS, but in only 51.6% of those without MDDS (p = 0.020).

Conclusion: Present study revealed that demographic findings and laboratory assessments are insufficient to diagnose genetically inherited diseases in children presenting with hepatic involvement. While one-fifth of the patients with suspected mitochondrial hepatopathies were diagnosed with MDDS, it is revealed that around half of patients can be diagnosed with CES panel.

Introduction: Peroxisome biogenesis disorders (PBDs) encompass a group of diseases marked by clinical and genetic heterogeneity. Phenotypes linked to PBDs include Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease (IRD), rhizomelic chondrodysplasia punctata type 1, and Heimler syndrome. PBD phenotypes manifest through hypotonia, developmental delay, facial dysmorphism, seizures, liver dysfunction, sensorineural hearing loss, and retinal dystrophy.

Methods: The proband underwent comprehensive clinical evaluation, followed by whole-exome sequencing (WES) coupled with copy number analysis (CNV), aimed at identifying potential disease-causing variants aligning with the observed phenotype.

Results: Our findings detail an individual exhibiting developmental delay, hearing loss, visual impairment, hepatomegaly, and splenomegaly, attributed to a biallelic deletion of exon 4 in the PEX26 gene. The WES analysis of the index case did not uncover any pathogenic/likely pathogenic single-nucleotide variations that could account for the observed clinical findings. However, the CNV data derived from WES revealed a homozygous deletion in exon 4 of the PEX26 gene (NM_001127649.3), providing a plausible explanation for the patient's clinical features. The exon 4 region of PEX26 encodes the transmembrane domain of the protein. The transmembrane domain plays a crucial role in anchoring the protein within lipid bilayers, and its absence can disrupt proper localization and functioning. As a result, this structural alteration may impact the protein's ability to facilitate essential cellular processes related to peroxisome biogenesis and function.

Conclusion: The index patient, which presented with hearing loss, retinal involvement and hepatic dysfunction in adolescence age, has atypical clinical course that can be considered unusual for Zellweger syndrome (ZS) and IRD phenotypes, and its rare genotypic data (in-frame single exon deletion) expands the PBD disease spectrum. This study revealed for the first time that PEX26 protein transmembrane domain loss exhibits an unusual course with clinical findings of IRD and ZS phenotypes. WES studies, incorporating CNV analyses, empower the identification of novel genetic alterations in genes seldom associated with gross deletion/duplication variations, such as those in the PEX26 gene. This not only enhances diagnostic rates in rare diseases but also contributes to broadening the spectrum of causal mutations.

Introduction: Inherited 5-oxoprolinase (OPLAH) deficiency is a rare inborn condition characterized by 5-oxoprolinuria. The inherited condition of 5-oxoprolinuria, or pyroglutamic aciduria, is primarily caused by mutations in the genes that encode glutathione synthetase (GSS) and 5-oxoprolinase (OPLAH), which are enzymes involved in the gamma-glutamyl cycle in glutathione metabolism. We report a 3-year-old male patient with epilepsy and speech difficulty diagnosed as primary 5-oxoprolinuria due to a novel OPLAH gene mutation.

Case presentation: A 3-year-old boy who was delivered at full term in an uncomplicated birth to consanguineous parents presented with epilepsy at the age of 2 years. He did not speak fluently. He was using 5-10 words with decreased language fluency. His past medical history revealed postnatal macrocephaly, hydrocephalus, and well-controlled epilepsy with levetiracetam. Progressive cerebral atrophy, hypomyelination, ventriculomegaly, and corpus callosum hypoplasia were striking features in brain MRI. A urine sample was sent for organic acid analysis by gas chromatography-mass spectrometry (GC-MS); quantitation of 5-oxoproline by stable isotope dilution gave a value of 177.9 mmol/mol creatinine (reference values 25.8-92.2). Molecular genetic analysis of the OPLAH gene revealed a novel homozygous variant (OPLAH (NM_017570.5): c.1909C>T p.Arg637Trp).

Conclusion: We conclude that inherited 5-oxoprolinase deficiency is not a benign biochemical condition, and patients with 5-oxoprolinuria should be screened for it. The nature of this inherited metabolic disorder must be determined through long-term observation. We wish to emphasize the significance of molecular genetic analysis in symptomatic patients with persistently elevated levels of 5-oxoproline in the urine, as measured by organic acid analysis.

Introduction: Sanfilippo syndrome or mucopolysaccharidosis type 3 (MPS-3) is a rare condition and its epidemiological data are still not defined. MPS-3 is linked to a deficiency in enzymes involved in heparan sulfate degradation. This biomolecule is neurotoxic and its accumulation underlies the severe central nervous system degeneration observed in this disease.

Methods: Here, we describe 15 Turkish patients with MPS-3A or MPS-3B subtypes. Clinical data upon the diagnosis and during the follow-up as well as molecular characterization are reported.

Results: Two and ten distinct variants were identified in SGSH and NAGLU gene sequences, respectively. Six variants (NAGLU NM_000263.3:c.532-?_c.764+?del, NAGLU NM_000263.3: c.509G>T, NAGLU NM_000263.3: c.700C>G, NAGLU NM_000263.3:c.507_516 del, NAGLU NM dises_000263.3: c.1354 G>A, NAGLU NM_000263.3: c.200T>C) have been previously published and 6 are novel (SGSH NM_000199.4: c.80T>G, SGSH NM_000199.4: c.7_16del, NAGLU NM_000263.3: c.224_235del, NAGLU NM_000263.3: c.904G>T, NAGLU NM_000263.3: c.626C>T, NAGLU NM_000263.3: c.1241A>G). SGSH NM_000199.4:c.7_16del variation might be caused by a founder effect.

Conclusion: Due to the high rate of consanguinity in Turkey, the incidence of Sanfilippo syndrome might be higher compared to other populations worldwide. Our results contribute to the characterization of rare diseases in Turkey and to improve our knowledge of the clinical, molecular, and epidemiological aspects of MPS-3 disease.