Molecular Syndromology最新文献

Introduction: Complex hereditary spastic paraplegias (HSPs) are defined by progressive spasticity with diverse neurological manifestations, complicating the diagnostic process. Pathogenic variants in genes encoding subunits of the adaptor protein complex-4 (AP4), including the AP4S1 gene, have been implicated in a subset of HSPs.

Case presentation: We report three siblings with complex HSP harboring pathogenic AP4S1 gene variants, focusing on the clinical characteristics and the diagnostic challenges and pitfalls. The patients exhibited common clinical features such as progressive spasticity, distinctive craniofacial features, and neurodevelopmental delays. Neuroimaging findings included agenesis of the corpus callosum and ventricular enlargement in two siblings, whereas one sibling demonstrated normal brain imaging. Initially, these cases were misdiagnosed as cerebral palsy, leading to unwarranted surgical interventions for tethered cord syndrome. Copy number variation analysis identified homozygous deletions in the AP4S1 gene.

Conclusion: In patients with progressive spasticity, seizures, distinctive craniofacial features, and neuroimaging anomalies, AP4S1-related HSP should be considered in the differential diagnosis. Enhanced awareness and further studies are vital for improving diagnostic precision and management of these intricate neurogenetic disorders.

Introduction: The lamin-B receptor (LBR) gene has two primary functions: maintaining the structural integrity of the nuclear envelope and playing a role in cholesterol biosynthesis. Heterozygous variants in the LBR gene have been associated with Pelger-Huët anomaly (PHA, OMIM #169400), while homozygous or compound heterozygous mutations have been associated with rhizomelic skeletal dysplasia, with or without PHA (OMIM #618019) and Greenberg dysplasia (OMIM #215140).

Case presentation: We report a 4-year-old boy presenting with short stature and short limbs and his mother exhibiting milder findings. Genetic analysis revealed a heterozygous c.1640A>G (p.Asn547Ser) and c.43C>T (p.Arg15*) variants in the LBR gene in both the boy and his mother. The father was identified as a heterozygous carrier of the c.43C>T (p.Arg15*) variant. Peripheral blood smears confirmed the PHA in the patient and his parents.

Conclusion: The phenotypic differences observed between the mother and male child in our study highlight the genetic variability and regressive nature of LBR-related skeletal dysplasias. This report shows the complexity of LBR-related phenotypes and expands the clinical spectrum of LBR mutations in rhizomelic skeletal dysplasia with PHA.

Background: Joubert syndrome type 33 (JBTS33) is a rare autosomal recessive disorder characterized by developmental delay, severe renal disease, hypotonia/ataxia, cerebellar vermian hypoplasia/aplasia, optic nerve atrophy, renal atrophy, and the "molar tooth sign" on imaging. Nearly 40 genes associated with Joubert syndrome have been identified, including CEP290, TMEM216, TMEM67, AHI1, and CC2D2A.

Methods: We report a consanguineous family with JBTS33 diagnosed through whole-exome sequencing. A novel biallelic homozygous nonsense mutation (ENST00000326291.11: c.1231C>T; p.Arg411Ter) in progesterone-induced blocking factor 1 (PIBF1) was identified.

Results: Our study included 3 patients with the same homozygous mutation in PIBF1, which contributed to clinical features such as psychomotor issues, dysmorphic features, hypotonia/ataxia, kidney failure, and possibly seizures. All 3 patient seizures have been eliminated after phenobarbital administration. This mutation has not been reported in public databases.

Conclusion: This study confirmed PIBF1 as a disease-causing gene for JBTS33, expanding the molecular and clinical spectrum of JBTS. Our findings underscore the importance of identifying the genetic underpinnings and phenotypic expansions of PIBF1 mutations. Enhanced diagnostic awareness can facilitate early intervention and management. Further research is required to elucidate the relationship between PIBF1 mutations and associated clinical manifestations.

Introduction: Cornelia de Lange syndrome is a rare congenital malformation syndrome characterized by prenatal-onset growth retardation, with typical facial findings that include bushy eyebrows, synophrys, long and thick eyelashes, ptosis, anteverted nostrils, long philtrum, and thin and downward sloping vermilion. The syndrome is caused by mutations in NIPBL, SMC1A, SMC3, RAD21, HDAC8, and ANKRD11 genes encoding cohesin complex proteins that maintain a chromatin structure in cell proliferation. In recently reported cases, new genes that are not involved in the cohesin complex but clinically cause CdLS have been identified. With these newly identified genes, the term chromatinopathies has been offered for this syndrome as it is more inclusive. Patients with the syndrome are classified as classical CdLS or CdLS-like phenotype according to their clinical features.

Methods: The clinical and molecular results of 17 new cases of CdLS are reported.

Results: The patients, who were between 2 months and 12 years of age, all had unique facial findings as well as growth retardation. Congenital malformations accompanying the syndrome in the patients were different. The molecular analysis showed genetic etiology in 13 patients, of which 2 were deletions and 11 were pathogenic missense variants in the NIPBL, HDAC8, and SMC1A genes and of these variants, some had not been reported previously.

Conclusion: By presenting the clinical and molecular results of these CdLS cases, it was aimed to expand the clinical spectrum, contribute to a better understanding of the genotype-phenotype relationship, and highlight the importance of molecular methods used in the diagnosis of genetic diseases.

Introduction: Chromosomal microarray analysis (CMA) allows the detection of submicroscopic chromosomal abnormalities such as unbalanced translocations and inversions. In recent years, its use in prenatal diagnosis has been implemented when certain ultrasound findings are detected. The purpose of this study was to analyze and describe the imbalances detected in prenatal samples collected from pregnancies followed in our center for having the indication to perform diagnosis using CMA.

Material and method: On a population of pregnant women of 13,685, 216 CMAs were performed on chorionic villi and amniotic fluids during the period 2019-2023. The inclusion criteria were normal screening of common aneuploidies and at least one of the following features: nuchal translucency higher than percentile 99, fetal abnormalities, early-onset fetal growth restriction, parents' history of chromosomal imbalances, or cases with chromosomal imbalances. When a relevant variant was detected, it was analyzed in the parents' fetus and when available, the phenotype of the born children was collected.

Results: Pathogenic copy number variations (CNVs) were detected in 13 of 216 samples (6%). In a single sample, two concurrent CNVs were detected. Isolated CNVs had OMIM numbers and corresponded to already reported syndromes. Seven variants of unknown significance (3.7%) were observed. The study of the parents showed that 14 of 21 variants identified had arisen de novo (one pathogenic and five unknown CNVs had been inherited from an apparently healthy parent). Three microduplications specially drew our attention: duplication 5q35.2 which encompassed MSX2 gene (because the reported phenotype is not consistent with what is expected for the genomic region) and duplications 1q21.1 and 16p11.2 (due to the ultrasound findings detected in fetuses had recently been postulated to be associated with these CNVs).

Conclusion: The phenotype of CNVs identified in prenatal samples is highly variable prenatally, like postnatally. Some findings may be part of the syndromes to which they give rise and some phenotypes may be pending to define. Further studies are needed to better define these variants and to understand how haploinsufficiency or over-expression of genes included in these regions can cause such complex phenotypes.

Introduction: Spondyloepiphyseal dysplasia tarda (SEDT) is an inherited disorder that is typically diagnosed in childhood or adolescence. It is characterized by disproportionate short stature and premature osteoarthritis, and it frequently affects males. Here, we described a novel nonsense mutation, c.406A>T; p(Lys136Ter), in TRAPPC2 (NM_001011658.4) in a Turkish patient with X-linked SEDT.

Case presentation: A 15-year-old boy, born to non-consanguineous Turkish parents, exhibited a decline in height velocity over 3 years and complained of back pain despite minimal physical activity. Growth and development were normal until adolescence, with the patient's weight at 35 kg (SDS -3.85), height at 134 cm (SDS -5.44), and a predicted adult height of 137.6 cm. Dysmorphic facial features, microtia, synophrys, hypotelorism, and barrel chest were noted. Radiological examination revealed osteopenic bone structure, hypoplastic odontoid process, platyspondyly, scoliosis, short femoral necks, and coxa vara. Genetic analysis identified a hemizygous novel stop codon mutation (c.406A>T; pLys136Ter) in TRAPPC2, also detected as heterozygous in the patient's mother.

Conclusion: In adolescence or childhood, X-linked SEDT should be considered in cases of disproportionate short stature, short trunk, osteoarthritis, and a family history that is appropriate for X-linked inheritance. Skeletal survey should be performed to suspect SEDT, and radiological findings may support diagnosis.

Background: Aminoacyl-tRNA synthetases are highly conserved proteins that catalyze the tRNA aminoacylation reaction to produce aminoacyl-tRNAs involved in protein synthesis, which are required to translate cytoplasmic and mitochondrial proteins. The mt-ARS genes encode the mitochondrial aminoacyl-tRNA synthetase (mt-ARSs), and variants in mt-ARS genes affect mitochondrial protein synthesis. This can impair the translation of mitochondrial proteins, adversely affecting oxidative phosphorylation and leading to related diseases. To date, 19 mt-ARS genes have been identified and found to be strongly associated with the development of mitochondrial disorders. Hearing loss (HL) is one of the most common chronic conditions in children and a leading cause of communication disorders. Genetic studies of sensorineural HL are critical to diagnosing and treating sensorineural HL. The relationship between mt-ARS genes and sensorineural HL is gradually surfacing as cases of HL phenotypes caused by variants in the mammalian mt-ARS genes continue to be reported. Seven mt-ARS genes have been reported to contribute to various hereditary sensorineural HL.

Summary: This article reviews studies on mitochondrial aminoacyl-tRNA synthetase, mt-ARS genes, and variants associated with HL phenotypes. Investigating their genetic characteristics provides deeper insights into the pathophysiology and molecular mechanisms of sensorineural hearing loss.

Key messages: Disease phenotypes resulting from variants in mt-ARS genes exhibit significant clinical heterogeneity. The varying degrees of sensorineural HL phenotypes caused by mt-ARS gene variants warrant the attention of otologists and researchers. At least seven of the currently reported mt-ARS genes are associated with sensorineural HL. However, the molecular mechanisms by which these genes contribute to HL remain incompletely understood. Further studies of the mt-ARS genes still await additional case reports, as well as related model animal studies and combined functional studies.

Introduction: Inherited glycosylphosphatidylinositol biosynthesis defect is considered a subset of the congenital glycosylation disorder that results from mutations in the genes encoding proteins participating in glycosylphosphatidylinositol biosynthesis and modification. Glycosylphosphatidylinositol anchor proteins play important roles in numerous cellular processes including neurogenesis, cell adhesion, immune response, and signaling. Hyperphosphatasia with mental retardation syndrome-3 is one of the glycosylphosphatidylinositol anchor defects, characterized by moderate to severe intellectual disability, dysmorphic features, hypotonia, seizures, and persistent hyperphosphatasia. The aims of this study were to investigate the clinical implications of the PGAP2 gene and identify the severe phenotype.

Case presentation: A male patient with dysmorphic features, neurodevelopmental delay, seizures, hearing loss, Hirschsprung disease, central fever, and elevated alkaline phosphatase was included in the study. The magnetic resonance imaging showed cerebral atrophy and corpus callosum hypoplasia. The whole-exome sequencing analysis of the individual and Sanger sequencing were performed for segregation. Additionally, next-generation sequencing, whole transcriptome sequencing, and homology modeling and analysis were performed. Whole-exome sequencing revealed a homozygous c.651C>G (p.His217Gln) in the PGAP2 gene. The Sanger sequencing confirmed the parents were heterozygous. There is no splicing variant detected by whole transcriptome sequencing. The AlphaFold model was interpreted hypothetically. It observed the substitution of histidine, with glutamine, and may affect the stability of protein.

Discussion: Homozygous PGAP2 mutations in the patient we reported in our study resulted in a severe clinical picture including severe developmental delay and intellectual disability, severe epilepsy, dysmorphic features, central fever, biochemical, hormonal, and immunological abnormalities. This patient would be the youngest case published in the literature. We showed that the instability of mutant PGAP2 protein that causes hyperphosphatasia with mental retardation syndrome-3 leads to more severe phenotypes.

Introduction: Beckwith-Wiedemann syndrome (BWS, MIM#130650) is an overgrowth syndrome characterized by macroglossia, omphalocele, macrosomia, and a predisposition to neoplasia. The etiology of BWS involves genetic and epigenetic alterations in the 11p15 region of the genome. In this study, we investigated how the International Consensus Clinical Scoring System (BWSICS) score can be used in clinical and molecular evaluations and examined its contribution to diagnostic processes.

Methods: This retrospective study included BWS patients who have been followed up in the pediatric genetics clinic of a center in the last 10 years. Clinical and molecular outcomes including chromosome analysis, microarray analysis, and MS-MLPA testing were evaluated. BWSICS scores were calculated for each patient based on their clinical symptoms.

Results: The study evaluated 18 patients who met BWS diagnostic criteria aged between 1 day and 10 years. The main presentations were macroglossia in 4 patients, omphalocele with macroglossia in 5 patients, and hypoglycemia in 2 patients and all but 1 patient was macrosomia. Significant congenital malformations included omphalocele and visceromegaly in 5 patients each. Hepatoblastoma was observed in 1 patient and 1 patient died due to sepsis. Two patients had autism spectrum disorder while the others had normal neuromotor development. According to the BWSICS, patients' scores ranged from 5 to 11. Molecular analysis revealed methylation alterations in 13/16 patients.

Conclusion: This study examined the effectiveness of the BWSICS score in the diagnosis and follow-up of BWS in combination with clinical and molecular evaluation. This score provides a broad assessment in the diagnosis of BWS and can be considered as an important tool in clinical practice.

Introduction: Congenital heart diseases are a group of diseases present at birth, including anatomical and physiological abnormalities of the heart. They are the most common birth defects observed in the populations. The etiology is quite diverse. Although they mostly show a multifactorial inheritance pattern, chromosome abnormalities, copy number variations, single gene diseases, and environmental factors are involved in the etiology. Even though the etiology can be detected at a higher rate in syndromic cases, it has not been elucidated in most syndromic and non-syndromic cases. Our study aimed to detect copy number variations in syndromic and non-syndromic cases through chromosomal microarray analysis, to reveal the diagnostic value of the method, and to determine possible new loci.

Methods: Patient files, photographs, and laboratory results of 85 cases (55 syndromic and 30 non-syndromic) who had congenital heart disease and chromosomal microarray analysis were retrospectively evaluated. The differences between the groups were analyzed with Chi-square and Mann-Whitney U tests.

Results: Pathogenic/likely pathogenic copy number variations were detected in 32.7% (18/55) of the syndromic case group and 6.7% (2/30) of the non-syndromic case group. The diagnostic efficacy of chromosomal microarray analysis in the diagnosis and the age at the time of admission were statistically significant between groups.

Conclusion: Our study suggest that the chromosomal microarray analysis is a valuable diagnostic tool to elucidate the etiology of congenital heart diseases.