Heterozygous Variants Research Articles

HTRA1-related cerebral small-vessel disease causes cerebral microbleeds on the brainstem surface

Background and objectivesCerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) has recently been known as HTRA1-related cerebral small-vessel disease (CSVD), it is caused by variants in HTRA1. Recently, it has been reported to develop in heterozygotes with some variants of the gene. Multiple prospective studies have reported that the frequency of heterozygous HTRA1 variants developing CSVD is 2 - 6.5 % in CARASIL. Heterozygous variant cases lack unique clinical features, have an older age of onset, and are difficult to detect. Characteristic findings are required to identify such cases. MethodMagnetic resonance imaging (MRI) images of cases that experienced cerebral infarction and carried heterozygous variants in HTRA1 were reviewed. ResultsFour cases of heterozygous HTRA1-related CSVD in two families (Family 1: c.754G > A, p.A252T; three males. Family 2: c.497G > T, p.R166L, one female). In all cases, white matter lesions with lacunar infarcts were observed in the periventricular and basal ganglia, external capsule, and brainstem. Moreover, T2 star weighted image (T2*WI) low presented dot-like lesions were present along the surface of the brainstem, which have only been reported in one homozygous case. Susceptibility-weighted imaging (SWI) was performed in two cases, and the dot-like lesions on T2*WI resembled a pearly tiara along the surface of the brainstem. ConclusionBrainstem surface on T2*WI low showed dot-like lesions, which are not generally observed in patients with stroke and can be characteristic of HTRA1-CSVD associated with heterozygous variant. The pathology requires further investigation for diagnosis.

Dysfunction of Calcyphosine-Like gene impairs retinal angiogenesis through the MYC axis and is associated with familial exudative vitreoretinopathy.

Familial exudative vitreoretinopathy (FEVR) is a severe genetic disorder characterized by incomplete vascularization of the peripheral retina and associated symptoms that can lead to vision loss. However, the underlying genetic causes of approximately 50% of FEVR cases remain unknown. Here, we report two heterozygous variants in calcyphosine-like gene (CAPSL) that is associated with FEVR. Both variants exhibited compromised CAPSL protein expression. Vascular endothelial cell (EC)-specific inactivation of Capsl resulted in delayed radial/vertical vascular progression, compromised endothelial proliferation/migration, recapitulating the human FEVR phenotypes. CAPSL-depleted human retinal microvascular endothelial cells (HRECs) exhibited impaired tube formation, decreased cell proliferation, disrupted cell polarity establishment, and filopodia/lamellipodia formation, as well as disrupted collective cell migration. Transcriptomic and proteomic profiling revealed that CAPSL abolition inhibited the MYC signaling axis, in which the expression of core MYC targeted genes were profoundly decreased. Furthermore, a combined analysis of CAPSL-depleted HRECs and c-MYC-depleted human umbilical vein endothelial cells uncovered similar transcription patterns. Collectively, this study reports a novel FEVR-associated candidate gene, CAPSL, which provides valuable information for genetic counseling of FEVR. This study also reveals that compromised CAPSL function may cause FEVR through MYC axis, shedding light on the potential involvement of MYC signaling in the pathogenesis of FEVR.

Association of FOXL2 and ERCC6 variants with premature ovarian insufficiency and their potential use in clinical IVF guidance

Premature ovarian insufficiency (POI) is the main cause of infertility in women. Some cases of POI are thought to be caused by genetic defects and the clinical outcomes of these patients are unknown. Here, we performed whole-exome sequencing of the peripheral blood of a cohort of 55 subjects with POI and identified one heterozygous missense variant in FOXL2 (c.1045G>C; p.Arg349Gly) and two heterozygous missense variants in ERCC6 (c.379G>A; p.Val127Ile and c.4223A>C; p.Glu1408 Ala) in four POI patients. All of these heterozygous mutations were predicted to be deleterious and were parentally inherited from their heterozygous fathers. The mRNA and protein expression of FOXL2 and ERCC6 were absent or decreased in the patients. The patients carrying the variants of FOXL2 (c.1045G>C; p.Arg349Gly) and ERCC6 (c.379G>A; p.Val127Ile) failed to conceive in two and four assisted reproductive cycles, respectively. Another patient and her sister carrying the ERCC6 (c.4223A>C; p.Glu1408 Ala) variant achieved good clinical outcomes after assisted reproductive therapy. Our findings support the possible roles of FOXL2 and ERCC6 in POI and might contribute to the genetic counseling of POI patients.

TARGETED SEQUENCING REVEAL TWO PATHOGENIC MUTATIONS IN LDLR AND APOE GENES IN PATIENT WITH FAMILY HYPERCHOLESTEROLEMIA: CASE REPORT

Familial hypercholesterolemia (FH) is a serious inherited disorder that can lead to early development of cardiovascular disease (CVD) due to the high blood cholesterol levels. In our study, we identified in FH patient likely pathogenic variant of LDLR and APOE genes. Interest in the homozygous state of FH is understandable given its rarity and severe health consequences. The homozygous state, when both LDL receptor alleles mutated, demonstrates even higher cholesterol levels and an earlier and more severe clinical course compared with the heterozygous state. In our study, we report an interesting case of homozygous FH due to its rare prevalence. Patient U., 16 years old, woman, admitted to the National Research Cardiac Surgery Center (NRCC), was diagnosed with FH, congenital heart disease (CHD), bicuspidal aortic valve (AV) type 1. Both parents (mother and father) were included for reliable analysis. DNA was isolated from the venous blood sample by using the column method of QIAamp DNA Mini Kit. Targeted NGS using TruSight Cardio panel for 174 genes was performed on MiSeq, Illumina. Identified genetic variants were classified according to the ACMG guidelines. Pathogenic variants were validated by Sanger sequencing. Additionally, databases of the VarSome and ClinVar were used for analysis. Sequencing of 96 genes and bioinformatics analysis identified 2 likely pathogenic variants - C526T:p.R176C in APOE and G295A:p.E99K in LDLR gene, 4 uncertain significance variants in APOB, TTN, COL3A1, NOTCH1 and 90 benign variants in APOB, TTN, LAMA4, MYPN, DMD. LDLR (G295A:p.E99K) and APOE (C526T:p.R176C) were validated and confirmed by Sanger sequencing in patients and her father and mother. The main function of the APOE gene is to make the protein apolipoprotein E, which is involved in fat metabolism. In our study, the patient had a heterozygous variant of СT polymorphism rs7412 in the APOE gene, which indicates the presence of a possible disorder of fat metabolism. LDLR gene encodes a protein called low-density lipoprotein receptor, which is responsible for the uptake of cholesterol-carrying lipoprotein particles in cells. In our study, a patient with a homozygous AA variant of the LDLR gene was found to be pathogenic. Disruption of the uptake of cholesterol-carrying lipoprotein particles in cells can have serious consequences for the body. This can lead to cholesterol accumulation in the blood and tissues, which in turn can contribute to the development of atherosclerosis and other CVD. We found that both parents had a heterozygous genotype of G295A:p.E99K in LDLR gene; and mother had a heterozygous genotype and father had a homozygous genotype of C526T:p.R176C in APOE gene. In our study, we found the genetic mutations - two likely pathogenic genetic variants LDLR (G295A:p.E99K) and APOE (C526T:p.R176C) associated with FH in patient with clinical phenotype of FH using TruSight Cardio targeted panel of 96 genes. Genetic testing using targeted NGS or whole exome sequencing would be useful for right diagnosis and might improve personalize treatment for these patients. To identify other genes associated with FH whole exome sequencing can be recommend. Supported by Committee of Science of the Ministry of Science and Higher Education of Republic of Kazakhstan (AP14869903), (BR21881970) and Nazarbayev University CRP (211123CRP1608).

Characterization of the Retinal Phenotype Using Multimodal Imaging in Novel Compound Heterozygote Variants of CYP2U1

To report the retinal phenotype in 2 patients simulating type 2 macular telangiectasis with new variants in CYP2U1 implicated in hereditary spastic paraplegia type 56 (HSP 56). Cross sectional case series study. Five members of a non-consanguineous family (parents and 3 male children) were investigated. All family members underwent a full ophthalmic evaluation and multimodal retinal imaging. Two family members demonstrating retinal anomalies underwent additional OCT angiography, dual wavelength autofluorescence and fluorescence lifetime imaging ophthalmoscopy, kinetic perimetry, fundus-correlated microperimetry, electroretinography, and electro-oculography. Whole-exome sequencing was performed in all 5 family members. To characterize the retinal phenotype in affected patients with variants in CYP2U1, using multimodal imaging: dual-wavelength autofluorescence, fluorescence lifetime, OCT angiography. The 2 siblings with compound heterozygous novel variants c.452C>T; p.(Pro151Leu), c.943C>T; p.(Gln315Ter) in CYP2U1 demonstrated parafoveal loss of retinal transparency and hyperreflectivity to blue light, redistribution of macular pigment to the parafoveal edge, photoreceptor loss, and fluorescence lifetime imaging ophthalmoscopy anomalies: a pattern compatible with that seen in macular telangiectasia type 2 (MacTel). One had manifest neurological abnormalities since early childhood; the second had no neurological abnormalities. Each parent and the third sibling were heterozygous for 1 variant and were neurologically and ophthalmically normal. These CYP2U1 variants are associated with a retinal phenotype very similar to that otherwise specific for MacTel, suggestive of possible links in the etiology and pathogenesis of these diseases. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

SLC12A1 variant c.1684+1 G>A causes Bartter syndrome type 1 by promoting exon 13 skipping.

Bartter syndrome type 1, an autosomal recessive genetic disorder, is caused by pathogenic loss-of-function variants in the SLC12A1 gene. It is characterized by metabolic alkalosis and prenatal-onset polyuria leading to polyhydramnios. We identified pathogenic gene in a 12-day-old newborn boy with Bartter syndrome type 1 using whole-exome sequencing. Sanger sequencing validated the identified variants. A minigene assay was performed to investigate the effect of a novel splice site variant on pre-mRNA splicing. We found a compound heterozygous variants in the SLC12A1 gene, consisting of a known pathogenic missense mutation (NM_000338: c.769 G>A; p.Gly257Ser) and a novel splice site variant (c.1684+1 G>A). In silico predictions and an in vitro minigene splicing assay demonstrated that the splicing variant c.1684+1 G>A abolished a consensus splice donor site of SLC12A1 intron 13, resulting in complete exon 13 skipping, translational frameshift, and premature termination codon, ultimately leading to loss of SLC12A1 function. Using a cell-based in vitro assay, we revealed the aberrant effect of the pathogenic splicing variant SLC12A1 c.1684+1 G>A on pre-mRNA splicing. Our findings expand the gene mutation spectrum of Bartter syndrome type 1, providing a basis for genetic diagnosis and the development of genetic medicines.

Functional pathogenicity of ESRRB variant of uncertain significance contributes to hearing loss (DFNB35)

Advances in next-generation sequencing technologies have led to elucidation of sensorineural hearing loss genetics and associated clinical impacts. However, studies on the functional pathogenicity of variants of uncertain significance (VUS), despite their close association with clinical phenotypes, are lacking. Here we identified compound heterozygous variants in ESRRB transcription factor gene linked to DFNB35, specifically a novel splicing variant (NM_004452.4(ESRRB): c.397 + 2T>G) in trans with a missense variant (NM_004452.4(ESRRB): c.1144C>T p.(Arg382Cys)) whose pathogenicity remains unclear. The splicing variant (c.397 + 2T>G) caused exon 4 skipping, leading to premature stop codon formation and nonsense-mediated decay. The p.(Arg382Cys) variant was classified as a VUS due to its particularly higher allele frequency among East Asian population despite disease-causing in-silico predictions. However, functional assays showed that p.(Arg382Cys) variant disrupted key intramolecular interactions, leading to protein instability. This variant also reduced transcriptional activity and altered expression of downstream target genes essential for inner ear function, suggesting genetic contribution to disease phenotype. This study expanded the phenotypic and genotypic spectrum of ESRRB in DFNB35 and revealed molecular mechanisms underlying ESRRB-associated DFNB35. These findings suggest that variants with high allele frequencies can also possess functional pathogenicity, providing a breakthrough for cases where VUS, previously unexplored, could be reinterpreted by elucidating their functional roles and disease-causing characteristics.

RPL26 variants: A rare cause of Diamond-Blackfan anemia syndrome with multiple congenital anomalies at the forefront

PurposeDiamond-Blackfan anemia syndrome (DBS) is a rare congenital disorder originally characterized by bone marrow failure with or without various congenital anomalies. At least 24 genes are implicated, the vast majority encoding for ribosomal proteins. RPL26 (ribosomal protein L26) is an emerging candidate (DBA11, MIM#614900). We aim to further delineate this rare condition. MethodsPatients carrying heterozygous RPL26 variants were recruited. In one of them, erythroid proliferation and differentiation from peripheral blood CD34+ cells were studied by flow cytometry, and RPL26 expression by quantitative reverse transcription polymerase chain reaction and immunoblotting. ResultsWe report on 8 affected patients from 4 families. Detailed phenotyping reveals that RPL26 is mainly associated with multiple congenital anomalies (particularly radial ray anomalies), albeit with variable expression. Mandibulofacial dysostosis and neural tube defects are potential features in DBA11, expanding the growing list of DBS abnormalities. In 1 individual, we showed that RPL26 haploinsufficiency was responsible for subclinical impairment in erythroid proliferation and enucleation. The absence of hematological involvement in 4 adults from this series contributes to the mounting evidence that bone marrow failure is not universally central to all DBS genes. ConclusionWe confirm RPL26 as a DBS gene and expand the phenotypic spectrum of the gene and the disease.

Genetic analysis of a Chinese pedigree affected with Achromatopsia due to variants of CNGA3 gene and a literature review

To explore the molecular basis for a Chinese pedigree affected with Achromatopsia (ACHM). A pedigree with ACHM which was admitted to the Women and Children's Hospital of Ningbo University on April 14, 2023 was selected as the study subject. Whole exome sequencing (WES) was carried out for the proband. Candidate variants were verified by Sanger sequencing and bioinformatic analysis. Related literature was reviewed, and clinical and genetic features of Chinese patients with ACHM due to variants of CNGA3 gene were summarized. WES revealed that the proband and his younger brother had both harbored compound heterozygous variants of the CNGA3 gene, namely c.1190G>T (p.Gly397Val) and c.2013del (p.Gly672ValfsTer69), which were respectively inherited from their mother and father. The c.1190G>T was a known pathogenic variant, whilst the c.2013del was unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.2013del variant was predicted to be likely pathogenic (PM2_Supporting+PVS1_Moderate+PM3+PP4). Literature review has identified 41 CNGA3 gene variants among 43 patients from 38 pedigrees, most of which were missense variants and had located in exon 8. Most patients were males, with nystagmus, photophobia, amblyopia and other symptoms during infancy/childhood as the main clinical manifestations, and there was a lack of genotype-phenotype correlation. The c.1190G>T (p.Gly397Val) and c.2013del (p.Gly672ValfsTer69) variants of the GNGA3 gene probably underlay the ACHM in the proband. Discovery of the c.2013del variant has enriched the mutational spectrum of the GNGA3 gene and provided a basis for genetic counseling and reproduction guidance for this pedigree.

Genetic analysis of a child with Primary hypertrophic osteoarthropathy

To explore the genetic etiology of a child with Primary hypertrophic osteoarthropathy. A child who was admitted to Zhongnan Hospital of Wuhan University on July 27, 2021 was selected as the study subject. Genomic DNA was extracted from peripheral blood samples of the child and his parents and subjected to whole exome sequencing. Suspected splicing variant was verified by Sanger sequencing of family members. In vitro function was validated through a minigene assay, whilst the suspected exonic deletion was validated by long-fragment PCR. Whole exome sequencing revealed that the child has harbored compound heterozygous variants of HPGD gene, including a heterozygous deletion (exon 3 del) derived from his father and a splicing variant (c.421+1G>T) derived from his mother. Long-fragment PCR verified that the child and his father had both harbored a 7 565 bp heterozygous deletion (c.218-1304_324+6156del), whilst the minigene assay proved that the splicing variant has resulted in skipping of exon 4. The heterozygous c.218-1304_324+6156del deletion and the c.421+1G>T splicing variant of the HPGD gene probably underlay the pathogenesis in this child. Above finding has enriched the mutational spectrum of the HPGD gene and provided a basis for genetic counseling and prenatal diagnosis for this family.

Genetic analysis of a child with Dias-Logan syndrome due to variant of BCL11A gene

To analyze the clinical and genetic characteristics of a child featuring Dias-Logan syndrome. A child with speech disorders and delayed psychomotor development from childhood who was admitted to the Rehabilitation Medicine Department of Children's Hospital Affiliated to Zhengzhou University in July 2022 was selected as the research subject. Clinical data of the child was collected. Genomic DNA was extracted from peripheral blood samples of the child and his parents. Potential variant was screened by whole exome sequencing, and candidate variant was verified by Sanger sequencing. The child has presented with global developmental delay, microcephaly, special facial features and behavioral problems. Genetic testing revealed a de novo variant of the BCL11A gene, namely c.561_567delACACGCA (p.Q187fs*7), which was classified as pathogenic (PVS1+PS2+PM2_Supporting). The heterozygous variant of BCL11A gene probably underlay the Dias-Logan syndrome in this child. Above finding has enriched the phenotypic and mutational spectrum of the BCL11A gene and provides a basis for genetic counseling and clinical decision-making.

Application of CNVPLUS-array custom microarray in genetic analysis of spinal muscular atrophy

To assess the application value of CNVPLUS-array for the genetic analysis of Spinal muscular atrophy (SMA). From June 2021 to December 2022, CNVPLUS-array technique was employed to test the SMN1 and SMN2 genes among peripheral blood samples from 17 suspected SMA patients, 18 core families with suspected SMA, and 25 healthy individuals. The results were compared with those of multiple ligation-dependent probe amplification (MLPA) assay. Samples with inconsistent results were subjected to nested PCR or comprehensive analysis of SMA. CNVPLUS-array has identified 35 SMA patients, 36 carriers, and 25 healthy individuals. In comparison, MLPA has identified 34 SMA patients, 36 carriers, and 26 healthy individuals. The two methods demonstrated a high consistency (Kappa = 0.968, P < 0.001). Additionally, CNVPLUS-array has identified one patient with compound heterozygous variants of SMN1 and one carrier with a [2+0] genotype. CNVPLUS-array not only can accurately determine the copy numbers of SMN1 and SMN2 genes, but also identify point mutations in SMN1 and [2+0] carriers, which has offered a new method for the genetic testing of SMA.

Genetic analysis and prenatal diagnosis for a Chinese pedigree affected with Autosomal dominant polycystic kidney disease

To explore the clinical phenotype and genetic etiology for a Chinese pedigree affected with Autosomal dominant polycystic kidney disease (ADPKD). A pedigree with ADPKD diagnosed at the Department of Gynaecology of the First Affiliated Hospital of Zhengzhou University in December 2020 was selected as the study subject. Clinical data of the pedigree was collected, and whole exome sequencing (WES) was carried out for the proband. Candidate variants were verified by Sanger sequencing of the proband and her relatives. Fetal ultrasonography showed increased volume and parenchymal echogenicity in both kidneys. The fetus was found to harbor c.11098C>T (p.R3700C) and c.11039T>C (p.F3680S) compound heterozygous variants of the PKD1 gene, which were respectively inherited from its mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PM1+PM2_supporting+PP3). The c.11098C>T (p.R3700C) and c.11039T>C (p.F3680S) compound heterozygous variants of the PKD1 gene probably underlay the ADPKD in the fetus. Above finding has provided guidance for the genetic counseling and prenatal diagnosis for this pedigree.

Genetic analysis of a child with pachygyria due to variant of ADGRG1 gen

To explore the genetic basis for a child with pachygyria. A proband who had visited Qinzhou Maternal and Child Health Care Hospital for pachygyria and mental retardation in June 2020 was selected as the study subject. Clinical data was collected. The child was subjected to whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing. The proband, a 4-year-and-6-month-old female, was clinically diagnosed with megagyrus deformity. WES revealed that she has harbored compound heterozygous variants of the ADGRG1 gene, namely c.781G>T (p.E261*) in exon 6 and c.1369A>C (p.S457R) in exon 11, which were verified by Sanger sequencing to be derived from her mother and father, respectively. Her younger sister was also heterozygous for the c.1369A>C (p.S457R) variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PVS1+PM2_ Supporting; PM1+PM2_Supporting+PM3+PP3). The c.781G>T (p.E261*) and c.1369A>C (p.S457R) compound heterozygous variants of the ADGRG1 gene probably underlay the pachygyria malformation in this child.

Clinical and genetic features of CMT2T in Italian patients confirm the importance of MME pathogenic variants in idiopathic, late-onset axonal neuropathies.

Since 2016, biallelic mutations in the membrane metalloendopeptidase (MME) gene have been associated with late-onset recessive CMT2 (CMT2T). More recently, heterozygous mutations have also been identified in familial and sporadic patients with late-onset axonal neuropathy, ranging from subclinical to severe. This indicates that the heterozygous MME variants may not be fully penetrant, or alternatively, that they may be a potential risk factor for neuropathy. Here, we describe the clinical, neurophysiological, and genetic findings of 32 CM2T Italian patients. The patients were recruited from four different Italian referral centers. Following a comprehensive battery of neurological, electrophysiological, and laboratory examinations, the patients' DNA was subjected to sequencing in order to identify any variants in the gene. Bioinformatic and modeling analyses were performed to evaluate the identified variants' effects. We observe a relatively mild axonal sensory-motor neuropathy with a greater impairment of the lower extremities. Biallelic and monoallelic patients exhibit comparable disease severity, with an earlier onset observed in those with biallelic variants. When considering a subgroup with more than 10 years of disease, it becomes evident that biallelic patients exhibit a more severe form of neuropathy. This suggests that they are more prone to quick progression. CM2T has been definitively defined as a late-onset neuropathy, with a typical onset in the fifth to sixth decades of life and a more rapidly progressing worsening for biallelic patients. CMT2T can be included in the neuropathies of the elderly, particularly if MME variants heterozygous patients are included.

Biallelic TYR and TKFC variants in Egyptian patients with OCA1 and new expanded TKFC features

BackgroundOculocutaneous albinism type1 (OCA1) is caused by the TYR gene's homozygous and compound heterozygous variants. TKFC gene variants cause triokinase & FMN cyclase deficiency syndrome with variable multisystemic disorders.ObjectivesTo determine the potential disease-causing variants in two deceased patients presenting atypical OCA1 features by demonstrating three generations for a single family. The two deceased neonates had severe skeletal abnormalities and fatal hypertrophic cardiomyopathy. We also explored the potential mechanisms for the causative relationship between TKFC and multisystem disorders.Patients and methodsDue to the new emerging symptoms that weren’t reported before with the TYR gene, the following methods were performed: Sanger sequencing for the TYR gene, followed by whole exome sequencing, co-segregation, and computational analyses.ResultsExtensive parental consanguinity was found, and consequently an autosomal recessive mode of inheritance was prioritized. Upon performing sequencing and segregation data, the following has been confirmed: positive co-segregation of nonsense homozygous NM_000372.5:c.346C > T p.(Arg116*) variant in TYR gene and multisystem disease-missense homozygous NM_015533.4:c.598G > A p.(Val200Ile) variant in TKFC gene in the two affected index patients who deceased due to hypertrophic cardiomyopathy. Using computational analysis, we found that c.598G > A p.(Val200Ile) pathogenicity has led to the failure of L2-K1 active site closure due to the potential differential fluctuation between valine and isoleucine residues. Subsequently, disruption of endogenous DHA phosphorylation was found. Two potential mechanisms exploring the causative relationship between TKFC gene and multisystem disorders have been suggested.ConclusionsThis study presented a first family with the co-existence of biallelic variants in TYR and TKFC genes associating severe skeletal abnormalities and lethal hypertrophic cardiomyopathy. Neither of these genes would have been pursued in the standard genetic counseling. Such discovery is paving the way for more efficient genetic counseling. Comparing TKFC results with literature data showed that our relevant expanded TKFC variant is the 3rd worldwide.

Shwachman-Diamond syndrome: A case report.

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive genetic disease, the diagnosis is a big challenge for clinician, as the clinical manifestations of the disease are diverse. Here, we report a girl who diagnosed with SDS with the symptoms of recurrent fever, elevated transaminase levels, and granulocytosis. The aspects of diagnosis and treatment were discussed and a literature review was conducted. A 15-month-old girl admitted to our hospital because of recurrent fever, granulocytopenia, and elevated transaminase levels. The compound heterozygous variant of Shwachman-Bodian-Diamond syndrome c.258 + 2T > C:p.84Cfs3 and c.96C > G:p.Y32* were detected after sequencing the blood samples from the patient and her parents. Finally, she was diagnosed with SDS and she was treated with compound glycyrrhizin, granulocyte-colony stimulating factor, and antibiotic in the case of co-infection. During the follow-up, her liver function showed the level of transaminases decreased and she rarely had infection after the age of 15 months although neutropenia is still present. Patients with SDS lacks typical clinical symptoms, which presents a huge challenge for clinicians. Genetic testing techniques is playing an important role in the diagnosis of diseases. This patient without typical clinical manifestations such as exocrine pancreatic insufficiency and skeletal abnormality, we report this case aimed to strengthen the understanding of the disease.

A novel heterozygous missense variant of PANX1 causes human oocyte death and female infertility

Pannexin1 (PANX1) is a highly glycosylated membrane channel-forming protein, which has been found to implicate in multiple physiological and pathophysiological functions. Variants in the PANX1 gene have been reported to be associated with oocyte death and recurrent in vitro fertilization failure. In this study, we identified a novel heterozygous PANX1 variant (NM_015368.4 c.410 C > T (p.Ser137Leu)) associated with the phenotype of oocyte death in a non-consanguineous family, followed by an autosomal dominant (AD) mode. We explored the molecular mechanism of the novel variant and the variant c.976_978del (p.Asn326del) that we reported previously. Both of the variants altered the PANX1 glycosylation pattern in cultured cells, led to aberrant PANX1 channel activation, affected ATP release and membrane electrophysiological properties, which resulted in mouse and human oocyte death in vitro. For the first time, we presented the direct evidence of the effect of the PANX1 variants on human oocyte development. Our findings expand the variant spectrum of PANX1 genes associated with oocyte death and provide new support for the genetic diagnosis of female infertility.

A novel variant of biallelic MME gene associated with autosomal recessive late-onset distal hereditary motor neuropathy in Chinese families

Distal hereditary motor neuropathies (dHMN) are a group of heterogeneous diseases and previous studies have reported that the compound heterozygous recessive MME variants cause dHMN. Our study found a novel homozygous MME variant and a reported compound heterozygous MME variant in two Chinese families, respectively. Next-generation sequencing and nerve conduction studies were performed for two probands. The probands in two families presented with the muscle weakness and wasting of both lower limbs and carried a c.2122 A > T (p.K708*) and c.1342 C > T&c.2071_2072delinsTT (p.R448*&p.A691L) variant, respectively. Prominently axonal impairment of motor nerves and slight involvement of sensory nerves were observed in nerve conduction study. Our study reported a “novel” nonsense mutation and a missense variant of autosomal recessive late-onset dHMN and reviewed reported MME variants associated with dHMN phenotype.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes with coexisting nemaline myopathy: a case report

BackgroundMitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and nemaline myopathy are two rare genetic conditions. We report the first case reported in world literature with coexistence of both these rare disorders.Case presentationA 11-year-old previously healthy Sri Lankan male child, product of a nonconsanguineous marriage with normal development presented with acute onset short lasting recurring episodes of right-sided eye deviation with impaired consciousness. In between episodes he regained consciousness. Family history revealed a similar presentation in the mother at 36 years of age. Examination was significant for short stature and proximal upper and lower limb weakness. His plasma and cerebrospinal fluid lactate were elevated. Magnetic resonance imaging brain had evidence of an acute infarction in the right occipital territory. Sanger sequencing for common mitochondrial variants of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes confirmed this diagnosis. Whole exome sequencing revealed pathogenic compound heterozygous variants in NEB gene implicating in coexisting nemaline myopathy. Acute presentation was managed with supportive care, antiepileptics, and mitochondrial supplementation. Currently he is stable on daily supplementation of arginine and limb-strengthening physiotherapy. He is being monitored closely clinically and with serum lactate level.ConclusionGenetic diseases are rare. Coexistence of two genetic conditions is even rarer. Genetic confirmation of diagnosis is imperative for prediction of complications, accurate management, and genetic counseling.