Molecular Syndromology最新文献

[This corrects the article DOI: 10.1159/000547016.].

Introduction: 5-Oxoprolinuria is primarily suggestive of genetic defects in two enzymes belonging to the gamma-glutamyl cycle in the glutathione metabolism: the glutathione synthetase and the 5-oxoprolinase. 5-Oxoprolinase deficiency is a sporadic autosomal recessive disorder of the gamma-glutamyl cycle, primarily caused by pathogenic variants in the OPLAH gene. Low levels of 5-oxoproline can normally be detected in urine, although high levels are a clue for diagnosing 5-oxoprolinase deficiency. The clinical picture is not well defined due to the limited number of cases. Some authors questioned whether it is a real inherited metabolic disorder or only a nonspecific biochemical finding. Nephrolithiasis, enterocolitis, PMR, and microcytic anemia are the well-known clinical symptoms and signs of 5-oxoprolinuria (pyroglutamic aciduria).

Methods: We present 4 patients who were diagnosed with 5-oxoprolinuria that had different clinical symptoms and 3 out of 4 patients were siblings.

Results: In this study, 2 female and 2 male patients with 5-oxoprolinase deficiency were included. There were different clinical findings in the same family. Patients had unreported clinical symptoms such as growth retardation and drug-resistant epilepsy.

Conclusion: OPLAH gene mutations have been observed to cause different clinical findings in the same family. A correlation was found between urine 5-oxoproline levels and the severity of clinical findings.

Introduction: Turner syndrome is a complicated gonadal insufficiency, infertility, and endocrine disease caused by the partial to complete loss of one X chromosome. Women with Turner syndrome have been reported to show altered effector T-cell subgroups; however, the relationship between T-cell subgroups and chromosome type remains unknown.

Methods: In this study, we investigated immune abnormalities and karyotypes of Turner syndrome. Using flowcytometry, we examined the T-cell subsets of 20 women with Turner syndrome and 23 women serving as controls (without recurrent pregnancy loss), between July 2021 and June 2022. Background data of the women with Turner syndrome were also collected.

Results: Significantly lower levels of helper T-cells 1 and 2 were observed in women with Turner syndrome than in the control group (4.5 ± 2.88 vs. 8.54 ± 4.45, p < 0.05, 0.56 ± 0.38 vs. 0.97 ± 0.48, p < 0.05, respectively). With respect to karyotypes, deletion of a specific region, pseudoautosomal region 2, which typically escapes X-inactivation, might influence regulatory T cells (Treg) levels as copy number of PAR2 and Treg rate were positively correlated (r = 0.76).

Conclusion: Individuals with Turner syndrome showed an altered T-cell subset, which might be caused by the deletion of a specific part of the X chromosome, pseudoautosomal region 2. This finding suggests that women with Turner syndrome in a specific karyotype show altered T-cell subsets, and more cases are needed to determine whether these T-cell changes could influence pregnancy outcomes.

Introduction: Bi-allelic variants in the 17-hydroxysteroid dehydrogenase type 4 gene (HSD17B4) cause the extremely rare autosomal recessive disorder known as peroxisomal D-bifunctional protein deficiency (D-BPD) (#OMIM 261515). This protein mediates hydration and dehydrogenation in the peroxisomal fatty acid β-oxidation pathway. Because of this, very long-chain fatty acids (VLCFAs), branched fatty acids (pristanic acid), and bile acid components cannot be broken down without it. Clinically, it causes developmental delay with neonatal hypotonia, seizures, and dysmorphic features. The D-BPD is divided into four subtypes according to the region affected by the variant causing the disorder.

Case presentation: Two newborns presented with severe hypotonia, intractable seizures, and dysmorphic facial features (microretrognathia, hypertelorism). These cases showed high levels of VLCFAs and were diagnosed by next-generation gene sequencing tests. We found a known homozygous variant (c.46G>A/p.Gly16Ser) in the HSD17B4 gene of case 1, which had been linked to D-BPD type III before. Case 1 developed adrenal insufficiency during follow-up. In case 2, we discovered a novel homozygous variant (c. 559A>T, p. Ile187Phe) in the HSD17B4 gene in exon 8 that led to the development of D-BPD type III. The American College of Medical Genetics and Genomics (ACMG) classifies this missense variant as likely pathogenic.

Discussion: The D-BPD type III cases profiled in this report exhibit a severe phenotype, which includes dysmorphic facial features, severe hypotonia, and refractory seizures that manifest from birth. One month after the VLCFAs analysis revealed something suggestive of a peroxisomal disorder, a targeted gene panel analysis could confirm the diagnosis.

Introduction: Verheij syndrome is associated with a deletion on chromosome 8q24.3 region or PUF60 gene mutations. A variety of symptoms including feeding problems, microcephaly, joint laxity, intellectual disability, cardiac defects, and renal abnormalities are the characteristic features of the syndrome.

Case presentation: In the current report, 2 cases are presented with Verheij syndrome in different ages. With this study, we aimed to present the clinical findings of a likely pathogenic novel variant in the first case NM_078480.3(PUF60):c.297+1G>C, and in the second case a likely pathogenic heterozygous missense variant NM_078480.3(PUF60):c.47G>T p.(G16V).

Conclusion: A very rare syndrome - Verheij syndrome - is reported in 2 cases with genotype phenotype correlation in this report.

Introduction: RASopathies are a heterogeneous group of conditions of the RAS/mitogen-activated protein kinase pathway presenting with overlapping features such as growth deficiency, neurodevelopmental disorders, cardiac defects, craniofacial dysmorphisms, cutaneous and ocular abnormalities, and increased cancer risk.

Methods: This retrospective study analyzed the medical records regarding clinical and molecular data from 2018 to 2024 in a single center for rare diseases of individuals diagnosed with Noonan syndrome and related disorders previously submitted to diagnostic molecular analysis through next-generation sequencing techniques.

Results: Twenty-four patients were enrolled with an even sex ratio distribution and ages ranging from 1 month to 16 years at first evaluation. The main reason for referral was diagnostic assessment due to a combination of dysmorphic features (24/24; 100%), growth deficiency (18/24; 75%), neurodevelopmental disorders (15/24; 62.5%), and/or heart disease (13/24; 54.1%). Final diagnoses included 15 individuals with Noonan syndrome (nine with variants in PTPN11, two in SOS1, and one each in LZTR1, A2ML1, and MRAS, besides one with variants in both LZTR1 and SOS1), two with Noonan syndrome with multiple lentigines (both with variants in PTPN11), two with Neurofibromatosis-Noonan (NF1), two with cardiofaciocutaneous syndrome (BRAF), and one each with Noonan syndrome-like with loose anagen hair (PPP1CB), Noonan syndrome-like (CBL), and Costello syndrome (HRAS); one individual presented with a double diagnosis of Noonan and Klinefelter syndromes.

Conclusion: Three pairs of unrelated patients presented recurrent variants in the PTPN11 gene, partially concordant in phenotypic correlation among the pairs but not fully concordant compared to previously described cases in the literature. Undescribed features in this group included myopathy and megacolon in a patient with Noonan syndrome-like, hypogonadotropic hypogonadism, and azoospermia in a patient with Noonan syndrome-like with loose anagen hair, and schizophrenia in a patient with Costello syndrome. One patient with Noonan syndrome had a novel variant of the A2ML1 gene (c.1829G>A), but the variant was strictly of uncertain significance, while c.2033G>A in the LZTR1 gene and c.1A>G in the NF1 gene are variants for the first time associated with features of Noonan syndrome.

Introduction: Neurodevelopmental disorders (NDDs) due to the HECW2 (MIM:617245), the pathogenic variant, are extremely rare. HECW2-related disorder has been established through the identification of de novo variants in HECW2 gene in patients with NDDs with hypotonia, seizures, and absent language.

Case presentation: In this study, the clinical and genetic features of a Chinese girl with neurodevelopmental delay, developmental language disorder, and hypotonia are described. Trio whole exome sequencing revealed a novel likely pathogenic variant in HECW2 (exon26: c.4354G>A; p. Gly1452Ser) in the patient, while the variant was absent in her parents with Sanger sequencing.

Conclusion: Our objective was to identify the potential site of HECW2, combined with the literature review, to find the correlation between clinical phenotype and genotype.

Introduction: Epidermolysis bullosa (EB) comprises a diverse group of rare, incurable genetic disorders characterized by blistering of the skin. These conditions have variable clinical presentations and poorly understood genotypes and phenotypes. This study aimed to confirm the diagnosis of dystrophic epidermolysis bullosa (DEB) in a family and analyze gene-phenotype correlations.

Methods: The study involved 3 patients, two controls, and one member with an unknown phenotype. We performed whole exome sequencing (WES) on family members to identify EB-associated genes, with Sanger sequencing for validation.

Results: (1) WES revealed missense variants in the COL7A1 ([c.4274T>C.L1425P] and [c.3602G>A.R1201H]) genes in the family; although recorded in the dbSNP database, they have not been reported in previous articles and classified as of uncertain significance by InterVar. These findings were confirmed by Sanger sequencing. (2) Statistical analysis indicated a significant association between DEB and epidermolysis bullosa simplex with junctional epidermolysis bullosa (p = 0.031) in dominant and recessive inheritance patterns, respectively. However, no significant correlation was found between the clinical phenotype of DEB and variant types (nonsense and missense), inheritance patterns (dominant and recessive), or between familial and sporadic cases.

Conclusion: This study identified variants in the COL7A1 gene within Chinese families, expanding the variant spectrum of DEB. These findings lay the groundwork for improved genetic diagnosis and counseling.

Introduction: Mitochondrial DNA depletion syndromes encompass rare genetic disorders stemming from various gene defects, including encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13), an autosomal recessive condition linked to FBXL4 gene variants. Although its prevalence is estimated at 1/100,000-400,000, the mechanism behind MTDPS13 remains incompletely understood. Recent studies suggest FBXL4 variants disrupt mitophagy, contributing to its pathogenesis.

Case presentation: A 3-year and 4-month-old male presented with respiratory distress, diarrhea, and unconsciousness. His medical history revealed developmental delay and dysmorphic features. Physical examination unveiled characteristic dysmorphisms, while neurological assessment indicated abnormalities. Laboratory findings exhibited metabolic disturbances consistent with MTDPS13, confirmed by genetic analysis revealing a homozygous c.1555C>T FBXL4 variant.

Conclusion: FBXL4 defects, found in approximately 0.7% of suspected mitochondrial disease cases, lead to varied phenotypes with nonspecific facial dysmorphisms. The patient's presentation aligned with reported features, including growth delay, hypotonia, and developmental delay. Notably, the diagnosis occurred later than typical onset, highlighting the variability in disease manifestation. Treatment focused on symptom management, with dichloroacetic acid effectively addressing lactic acidosis. This case underscores the importance of considering mitochondrial diseases, particularly FBXL4-related MTDPS13, in patients presenting with metabolic disturbances and dysmorphic features. Early recognition facilitates appropriate management and genetic counseling for affected families.

Introduction: Weiss-Kruszka syndrome is a rare, autosomal dominant neurodevelopmental disorder caused by pathogenic variants in the ZNF462, located at chromosome 9p31.2. Clinically, it is characterized by craniofacial dysmorphism, global developmental delay, intellectual disability, short stature, congenital anomalies of the heart and brain, and feeding difficulties. The phenotypic spectrum is notably heterogeneous, with variable expressivity and occasional incomplete penetrance.

Case presentation: Herein, we report a novel de novo heterozygous frameshift variant in ZNF462, designated c.2924del; p.(Gln975ArgfsTer3) (NM_021224.6), identified in a pediatric patient.

Conclusion: Importantly, our patient presented with a congenital diaphragmatic hernia - an anomaly not previously described in association with Weiss-Kruszka syndrome. To date, 48 cases have been reported in the literature. Our findings further broaden the phenotypic spectrum linked to ZNF462 variants and emphasize the need for continued clinical and molecular characterization. Through the detailed documentation of this unique case, we aimed to enhance the understanding of the clinical variability and potential comorbidities associated with this emerging syndrome.