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Hydatidiform mole (HM) is a pathological pregnancy characterized by excessive trophoblast proliferation and the absence of embryonic tissue development, predominantly sporadic in onset. Recurrent hydatidiform mole (RHM) affects approximately 1%-4% of HM patients, among which familial RHM (FRHM) is extremely rare and classified as a monogenic autosomal recessive disorder. NLRP7 (NLR family, pyrin domain containing 7) is the major pathogenic gene for RHM, in which affected individuals have a profound impairment in fertility and a markedly elevated risk of malignant transformation. Yet mechanistic research remains constrained by ethical limitations in human embryo studies and the absence of animal models recapitulating HM phenotypes. Here, we report the generation and characterization of iPSC lines from FRHM patients harboring homozygous NLRP7 variants c.2078G > A (p.Arg693Gln) and c.2161 C > T (p.Arg721Trp), respectively. These cellular models offer a unique platform to dissect molecular pathways driving NLRP7-mediated reproductive failure, overcoming long-standing barriers in FRHM pathogenesis research.

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We present the case of an adult male with repeated episodes of post-exercise acute renal injury. His biochemical study revealed severe hypouricemia with very high fractional excretion of urate and a genetic study showed the presence of an undescribed homozygous variant: SLC2A9 c.999T > G (p.N333K). A study of the parents, who were clinically healthy, normouricemic, and non-consanguineous, revealed that they carried the same variant in heterozygosis. Of the patient's two sisters, one is healthy and homozygous for the reference allele, while the other, who exhibits the same homozygous variant as the index case, presents with hypouricemia but remains asymptomatic. This is likely attributable to her physical inactivity, a consequence of severe uncorrected hip dysplasia. The present study aims to shed light on the pathogenic potential of this variant, not previously described in Latin Americans, illustrating the pathophysiological sequence that originates from the genetic change in renal uric acid management and its relationship with physical exercise and consequent acute kidney injury (AKI).

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Rare monogenic diseases are increasingly identified in children with chronic kidney disease. We describe a consanguineous preterm male infant with a clinical picture of advanced kidney dysfunction and severe renal salt-wasting, highly suggestive of prenatal onset Bartter syndrome. Patient's follow-up was characterized by severe polyuria; episodes of hyponatremia, hypokalemia, and hypochloremia; and metabolic alkalosis and hyperuricemia. We found a homozygous pathogenic variant in the TFCP2L1 gene, a transcription factor required for normal kidney development, that regulates acid-base and salt-water homeostasis. To our knowledge, there is only one published case of a child with TFCP2L1 gene pathogenic variants with a similar phenotype. This report adds evidence to TFCP2L1 as a cause of monogenic kidney disorders. Rare kidney dysplasias may manifest as phenocopies of primary tubulopathies. Genetic diagnosis plays a major role and should be carefully considered in patients with refractory course to standard treatment to facilitate management and family counselling.

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OBJECTIVES: To report an unusual case of Wolcott-Rallison syndrome (WRS) due to a novel homozygous missense mutation c.1805G>T (p.Gly602Val) in the Exon 11 of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3) gene. CASE PRESENTATION: A 2-month-old infant, born to a consanguineous marriage presented to PICU with the manifestation of severe diabetic ketoacidosis (severe hyperglycemia, pH 6.984 + ketones in urine). Genomic sequencing analyses detected a novel homozygous missense variation in the Exon 11 of the EIF2AK3 gene that resulted in the amino acid substitution of valine for glycine at codon 602 (p.Gly602Val). A diagnosis of Wolcott-Rallison syndrome was confirmed. He was treated with fluid therapy and regular insulin infusion. The purpose of this case report is to highlight the novel mutation in the Exon 11 of the EIF2AK3 gene and to raise awareness for screening of pathogenic genetic variants in the EIF2AK3 gene in all patients with neonatal diabetes mellitus. CONCLUSIONS: In the evaluation of infants with diabetic ketoacidosis, genomic DNA sequencing analyses should be performed in all cases of neonatal diabetes mellitus for early diagnosis of Wolcott-Rallison syndrome.

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BACKGROUND: ANGPTL3 plays a key part in lipoprotein metabolism. Zodasiran, a liver-targeted RNA interference therapeutic, inhibits ANGPTL3 expression and reduces atherogenic lipoproteins through mechanisms independent of the LDL receptor (LDLR). This approach is relevant to patients with homozygous familial hypercholesterolaemia (HoFH) who have extreme elevations of LDL cholesterol due to markedly impaired LDLR function and, as a result, very high risk of premature adverse cardiovascular events. We aimed to evaluate the long-term safety and efficacy of zodasiran in patients with HoFH. METHODS: GATEWAY was an open-label, randomised, phase 2 study done at seven clinical sites in Australia, Canada, South Africa, and the USA. Patients aged 16 years or older with documented HoFH who were receiving stable lipid-lowering therapy, were on a low-fat diet, had a screening LDL cholesterol of 2·6 mmol/L (100 mg/dL) or higher, and had triglycerides less than 3·4 mmol/L (300 mg/dL) were randomly assigned (1:1) using a block design to receive subcutaneous injections of 200 mg or 300 mg zodasiran on day 1 and month 3. When a majority of patients completed 6 months of treatment, an interim, non-binding, aggregate analysis of efficacy and safety data was conducted according to an adaptive study design to decide whether a single dose could be used for longer-term evaluation. After 9 months of follow-up, patients could opt for long-term open-label extension for an additional 24 months of subcutaneous zodasiran 200 mg injections every 3 months, as established following the planned interim analysis. The primary endpoint was percentage change from baseline to month 6 in fasting LDL cholesterol and was assessed in all randomly assigned patients who received at least one dose of study drug. Safety was assessed in all patients who received one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT05217667, and is ongoing (recruitment has now ended). FINDINGS: Between April 1 and Nov 12, 2022, 18 patients (mean age 43·0 years [SD 19·4] and 14 [78%] White) were randomly assigned to receive zodasiran 200 mg (n=9) or 300 mg (n=9). Mean baseline LDL cholesterol concentration was 9·8 mmol/L (SD 5·7) despite background lipid-lowering therapy. At month 6, patients showed substantial dose-responsive reductions in fasting LDL cholesterol (mean -35·7% [SD 28·6; 95% CI -57·6 to -13·7] with 200 mg and -39·9% [18·1; -53·9 to -26·0]) with 300 mg, which was consistent with the interim results of more than 40% reduction in both groups. Following partial washout, all patients entered the open-label extension, in which zodasiran showed evidence of continued effect, with reductions in fasting LDL cholesterol (mean -40·7% [SD 22·3] for the pooled doses) observed for an additional 12 months, as the study was stopped early for business reasons. Reductions were greater in a subset of patients in whom lipid-lowering therapy included a PCSK9 inhibitor (mean -55·8% [SD 19·1] at month 6 of the randomised treatment period and -51·9% [11·6] at month 12 of the open-label extension). There were no drug discontinuations, drug-related severe adverse events, or deaths. In the randomised treatment period, treatment-emergent adverse events occurred in six (67%) of nine patients in the zodasiran 200 mg group and six (67%) of nine patients in the zodasiran 300 mg group, with the most frequent adverse events being nasopharyngitis (two [22%] vs two [22%]), dizziness (two [22%] vs one [11%]), and upper respiratory tract infections (one [11%] vs one [11%]). Adverse events occurred in 11 (61%) of 18 patients in the open-label extension, and the most frequent adverse events were COVID-19 (five [28%]) and nasopharyngitis (five [28%]). INTERPRETATION: Quarterly dosed zodasiran shows evidence of reductions in LDL cholesterol with a favourable safety profile, in patients with HoFH receiving background lipid-lowering therapy. Further investigation in phase 3 trials is warranted. FUNDING: Arrowhead Pharmaceuticals.

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We describe a patient with a homozygous loss-of-function mutation in NR1H4, presenting with idiopathic mild elevation of transaminases. His presentation differs from the limited previously reported cases of progressive familial intrahepatic cholestasis type 5 (PFIC5). Case report: A 7-year-old boy was admitted to our outpatient clinic due to persistently elevated transaminases since 12 months of age. While PFIC5 is typically a rapidly progressive disease requiring liver transplantation, this patient's laboratory results showed normal gamma-glutamyl transferase (GGT), international normalized ratio (INR), albumin, and alpha-fetoprotein (AFP) levels. Liver biopsy revealed only mild fibrosis. Over a two-year follow-up, he has remained stable with mild transaminase elevation. Conclusion: Infants with cryptogenic liver disease should be evaluated for NR1H4 mutations-associated PFIC5. This mutation may represent a novel metabolic etiology of idiopathic, mildly elevated transaminases.

Se describe un paciente con una mutación homocigota con pérdida de función en el gen NR1H4, que presentaba hipertransaminemia leve idiopática. El cuadro clínico difiere de los pocos casos reportados de colestasis familiar intrahepática tipo 5 (PFIC5 por la sigla en inglés). Caso clínico: un niño de 7 años de edad fue admitido en nuestro centro de atención ambulatoria, por hipertransaminasemia persistente desde los 12 meses de edad. La PFIC5 en su forma típica, es de progresión rápida y requiere trasplante hepático, pero en este paciente, los valores de gamma-glutamil transferasa, índice internacional normalizado, albúmina y alfa-fetoproteína fueron normales. La biopsia hepática mostró solo una fibrosis leve. Durante los dos años de seguimiento, el niño permaneció estable, con hipertransaminasemia leve. En niños con enfermedad hepática criptogénica, se deben evaluar las mutaciones del gen NR1H4 asociadas a la PFIC5. Esta mutación puede representar una nueva etiología metabólica de hipertransaminasemia leve idiopática.

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BACKGROUND AND AIMS: Diagnosis of Homozygous Familial Hypercholesterolaemia (HoFH) relies on untreated low-density lipoprotein-cholesterol (LDL-C) which is often unknown. We determine whether untreated LDL-C can be imputed from treated LDL-C in HoFH. METHODS: Two groups with HoFH were identified: Group 1 (n = 193) from Canada, Brazil and South Africa; Group 2 (n = 206) from the HoFH International Clinical Collaboration. Pre- and post-treatment LDL-C and lipid lowering therapy (LLT) intensity from Group 1 were used to develop a regression model and applied to treated LDL-C in Group 2 to impute pre-treatment LDL-C. The same process was performed in reverse. A final imputation model was created from combining both groups. RESULTS: There was a curvilinear relationship between the expected and observed % lowering of LDL-C on LLT (r = 0.3923, p < 0.0001, Standard Error [SE] = 23 %). Using this relationship, LDL-C was imputed from treated values and showed significant correlation with pre-treatment LDL-C (r = 0.71, p < 0.001; mean values 13.4 ± 4.7 [Standard Deviation] and 13.6 ± 7.3 mmol/L, respectively, ns). Concordance between actual and imputed values ≥ 10 or <10 mmol/L was 80 %. Whereas 36 % of patients had treated LDL-C ≥ 10 mmol/L, 64 % had treated or imputed pre-treatment LDL-C ≥ 10 mmol/L. CONCLUSIONS: In HoFH, the response to LLT can be quantified and used to impute untreated LDL-C from treated LDL-C. Imputation may augment awareness of possible HoFH in treated subjects lacking records of untreated LDL-C.

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Medullary thyroid carcinoma (MTC) can occur sporadically or as a hereditary disease. The latter often presents with a multiple endocrine neoplasia type 2 (MEN2) phenotype and is caused by germline-activating pathogenic variants in the RET proto-oncogene, whereas the former may harbor somatic-activating RET pathogenic variants. Here, we report a family with a germline RET V778I pathogenic variant. The proband was a 72-year-old woman with bilateral multifocal MTCs but without other MEN2 features. Germline RET analysis revealed a homozygous V778I pathogenic variant. Postoperative histopathological examination confirmed bilateral multifocal MTC with lymph node metastasis. The patient's parents were cousins. The patient had no family history of MTC or MEN2. Her three middle-aged children were heterozygous for the V778I pathogenic variant, had no symptoms or signs of MTC, and had normal serum calcitonin and CEA levels. The proband died of cardiac and pulmonary diseases at the age of 86, 15 years after surgery, without MTC recurrence. Unlike other dominant RET pathogenic variants, in which a single mutated allele is sufficient for tumor development, V778I may have weak oncogenic activity, requiring homozygosity to develop MTC. Therefore, prophylactic thyroidectomy is not recommended for heterozygous carriers. To the best of our knowledge, this is the second report of a family with MTC exclusively associated with a homozygous RET pathogenic variant. This is also the first report of a germline RET V778I pathogenic variant associated with MTC under homozygous conditions.

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Human papillomavirus (HPV)-independent oropharyngeal squamous cell carcinoma (OPSCC) is an aggressive cancer without established molecular prognosis. CDKN2A (encoding p16) deletion is a common genetic event in HPV-independent OPSCC. CDKN2A homozygous deletion is recognized as a poor prognostic factor in various tumors, such as gliomas, and methylthioadenosine phosphorylase (MTAP) immunostaining serves as a surrogate marker for it. Because MTAP is related to the methionine salvage pathway, various cancer cell lines with MTAP deletion have been reported to exhibit increased sensitivity to the pyrimidine analog 5-fluorouracil (5-FU). This study aimed to clarify the prognostic effect of the expressions and homozygous deletions of CDKN2A ( p16 ) and MTAP in 177 patients with OPSCC (106 HPV-positive and 71 HPV-negative) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). MTAP loss by IHC was observed in 25.3% (16/63) of HPV-negative/p16-negative OPSCCs, and FISH confirmed homozygous deletions of both CDKN2A and MTAP . All HPV-negative/p16-positive (n=8) and HPV-positive (n=106) OPSCCs did not exhibit MTAP deficiency. The prognosis of the HPV-negative/MTAP - loss group (n=16) was significantly better than that of the HPV-negative/MTAP-retained group (n=47) and was as favorable as that of the HPV-positive group (n=106). A similar trend was confirmed in patients with HPV-negative OPSCC who received pyrimidine-based chemotherapy (n=46). MTAP deficiency is closely associated with homozygous CDKN2A and MTAP deletions in HPV-negative/p16-negative OPSCCs. Furthermore, MTAP loss may be a favorable prognostic factor in HPV-negative OPSCC, and this paradoxical phenomenon might be explained by the enhanced efficacy of chemotherapy with pyrimidine analogs.

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The molecular genetic diagnosis of prelingual sensorineural hearing impairment (HI) is essential for genetic counseling and patient management. Effective diagnosis requires a knowledge of the genetic architecture of HI, which is often lacking. We established a cohort of 450 unrelated patients with familial (at least two affected relatives) severe-to-profound bilateral prelingual HI in five countries with high consanguinity rates: Tunisia, Jordan, Algeria, Morocco, and Mauritania (the TJAMM cohort). Recessive and dominant inheritance were observed in 92% and 8% of cases, respectively; 14% were syndromic. Genome analysis detected 211 different mutations (36% not reported before) in 49 deafness genes, and fully resolved 90% of cases of autosomal recessive isolated deafness (DFNB forms), 89% of the mutations being homozygous. The deafness genes involved were similar in different countries, but their mutations, except a few in GJB2 and LRTOMT, differed considerably, suggesting an overrepresentation of private mutations. Biallelic missense mutations in MYO7A, CDH23, PCDH15, USH1C cause either DFNB forms or Usher syndrome type 1 (USH1) (USH1/DFNB genes). Such mutations were overrepresented (13% of patients), highlighting the importance of distinguishing between these two mutation classes. We hypothesized that current difficulties might stem from the misclassification of certain mutations. By studying the 65 USH1/DFNB missense mutations reported to cause DFNB in the homozygous state, we identified some that, when associated with a loss-of-function mutation, resulted in USH1, a characteristic pattern of some recessive hypomorphic mutations. This reappraised classification of USH1/DFNB mutations has the potential to improve molecular diagnosis and patient management significantly.

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MLASA2 is a rare mitochondrial disorder with limited geographic representation in published medical literature. Here, we report the first confirmed case of MLASA2 in a Latin American 16-year-old male harboring a homozygous pathogenic variant p.(Asp311Glu) in the YARS2 gene. The patient presented with sideroblastic anemia and short stature, accompanied by other skeletal dysplasia features not previously associated with MLASA2, including epiphyseal dysplasia, rib edge widening, and poorly defined vertebral structures, but without lactic acidosis. Notably, the patient did not present exercise intolerance but recently exhibited reduced muscle strength. The p.(Asp311Glu) variant, located in the anticodon-binding domain of the mitochondrial tyrosyl-tRNA synthetase (Mt-TyrRS), was consistently predicted to be pathogenic by multiple in silico tools. Molecular modeling revealed that this variant destabilizes the 'KMSKS' motif, potentially compromising tRNA recognition fidelity and aminoacylation efficiency. Analysis of runs of homozygosity (ROH) revealed significantly elevated consanguinity (ROH: 31.93%), consistent with a consanguineous mating between biological parents. This case expands the geographic distribution of MLASA2, documents previously unreported phenotypes, suggests a novel pathogenic mechanism, and demonstrates the utility of genomic approaches for diagnosing rare mitochondrial disorders in the absence of complete clinical information and family history.

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BACKGROUND: APOE4 homozygotes with Alzheimer's have faster rates of cognitive decline and become symptomatic approximately a decade earlier. APOE2 is a protective variant with reduced likelihood of developing AD and a slower rate of decline. LX1001 is an adeno-associated viral vector investigational gene therapy (AAVrh.10hAPOE2) delivering the APOE2 gene into the central nervous system of APOE4 homozygotes to convert the brain APOE4 homozygous genotype to an APOE2/E4. METHOD: This is a Phase 1/2, dose escalation study (NCT03634007) evaluating the safety and tolerability of LX1001 in four ascending single-dose cohorts (C1-C4). LX1001 was administered into the cerebrospinal fluid (CSF) at the craniocervical junction. Enrollment criteria include APOE4 homozygotes, age ≥ 50, positive amyloid PET, CSF biomarkers consistent with AD, and mild cognitive impairment (MCI) to moderate dementia. Following the one-time dose, the CSF APOE2/E4 profile, fluid and imaging biomarkers were assessed at regular intervals over 12 months. RESULT: Fifteen participants were dosed: 50% MCI, 14% mild and 36% moderate dementia, at baseline. Twelve months of data are available for C1-C3 and 6 months for C4. Treatment with LX1001 was generally safe and well-tolerated. No events of amyloid related imaging abnormalities were observed. Post-treatment, APOE2 was expressed in CSF in all participants in a dose dependent manner. Interim results showed stabilization in CSF Aß42/40 and amyloid PET. There was a decrease in CSF t-tau, p-tau, and Tau PET. Full data results including 12-month data for C4 will be presented during the meeting. CONCLUSION: LX1001 is the first investigational gene therapy for APOE4 homozygotes. Data suggest LX1001 is generally safe and well tolerated with reduction in CSF tau biomarkers and Tau PET, measures that are highly correlated with cognitive decline.

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Background and Clinical Significance: Methyltransferase-like protein 5 (METTL5) is a conserved RNA methyltransferase responsible for catalyzing the N6-methyladenosine (m6A) modification of 18S ribosomal RNA, a process critical for ribosome biogenesis and translational regulation. Biallelic variants in METTL5 have been linked to autosomal recessive intellectual developmental disorder-72 (MRT72), typically presenting with microcephaly, intellectual disability, and speech delay. However, the association between METTL5 and isolated attention-deficit/hyperactivity disorder (ADHD) remains underexplored. Case Presentation: We report a 14-year-old Qatari female, born to consanguineous parents, who presented with microcephaly, speech delay, learning difficulties, and inattentive-type ADHD. Trio-based whole-genome sequencing identified a novel homozygous METTL5 variant (c.617G > A; p. Arg206Gln), with both parent's heterozygous carriers. The variant is extremely rare (gnomAD MAF: 0.0000175) and predicted to be deleterious (CADD: 23.7; SIFT: damaging; PolyPhen-2: probably damaging). Structural modeling localized the change within the SAM-dependent catalytic domain, predicting protein destabilization (ΔΔG = +1.8 kcal/mol). The affected residue is highly conserved (ConSurf score: 8), and protein-protein interaction analysis linked METTL5 with METTL14, METTL16, and ZCCHC4, key regulators of rRNA methylation. Conclusions: In silico evidence suggests that the p. Arg206Gln variant disrupts METTL5 function, likely contributing to the observed neurodevelopmental phenotype, including ADHD. This expands the clinical spectrum of METTL5-related disorders and supports its inclusion in neurodevelopmental gene panels.

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Restrictive dermopathy (RD) is a rare, lethal, congenital autosomal recessive laminopathy syndrome characterized by generalised tight translucent skin, dysmorphic facies, arthrogryposis multiplex congenita, and pulmonary hypoplasia. It is caused by mutations in either ZMPSTE24 or LMNA. Variants in these genes, which disrupt the production of lamin A, and hence the structural integrity of the nuclear envelope, can also cause survivable syndromes such as mandibuloacral dysplasia (MAD). We report the first son of non-related Caucasian parents delivered via emergency LSCS at 34 weeks following preeclampsia, gestational diabetes and polyhydramnios. Extraction was difficult due to arthrogryposis. At birth (weight 1.65 kg), he showed the typical features of RD. Genetic testing revealed a homozygous pathogenic ZMPSTE24 frameshift variant c.1085dup p. (Leu362PhefsTer19) previously reported in mandibuloacral dysplasia (Agarwal AK, Fryns JP, Auchus RJ, Garg A. Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet 2003;12:1995-2001). Parents were heterozygous carriers. The baby received palliative care and died on day 2. The longest survival in RD is 120 days, in contrast to other laminopathies. Similar or identical mutation within the LMNA gene produces varied phenotypes which expands the spectrum. Currently, there is no curative therapy for RD. Our main aim to diagnose this condition is to offer counselling, genetic testing for future pregnancies, prevent unnecessary interventions and support the family through compassion and dignity.

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BACKGROUND: The Kell null (K0) is a rare phenotype characterized by the absence of all Kell blood group antigens. Individuals with K0 are often identified after developing anti-Ku, an antibody associated with hemolytic transfusion reactions (HTR) and hemolytic disease of the fetus and newborn (HDFN). Transfusion management in this population is particularly challenging as compatible blood is difficult to find. It is crucial to adopt safe and reliable treatments for preoperative blood management. STUDY DESIGN AND METHODS: We describe a K0 woman with potent Ku alloantibody preparing for surgery. Kell antigen typing and titers of anti-Ku were detected by standard serologic techniques. Polymerase chain reaction (PCR) and DNA sequencing of the KEL coding region were performed on her genomic DNA. Therapeutic plasma exchange (TPE) was initiated for five sessions to reduce the high anti-Ku titers before surgery. RESULTS: The red blood cells (RBCs) phenotype of the Kell blood group was identified as K- k-; Kp(a- b-). DNA sequence analysis revealed the patient was homozygous for a nucleotide deletion, NM_000420.3:c.855delT (p.L286*) in exon 8 of the KEL gene. After TPE, the anti-Ku titers decreased from 1:1600 to 1:400. A rebound phenomenon was noted during the procedures. DISCUSSION: We identified a novel homozygous KEL variant causing K0 phenotype in a Chinese woman with Ku alloimmunization. TPE proved to be effective for decreasing anti-Ku titers. However, the rebound of antibodies should be considered when using TPE to decrease the antibody titers. This report demonstrates a new attempt in preoperative transfusion management for patients with rare alloantibodies.

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PURPOSE OF REVIEW: The review focusses on the role of liver transplantation, and rarely combined liver and heart transplantation, in the current management of homozygous familial hypercholesterolaemia (HoFH). RECENT FINDINGS: The review features world-wide reports published during the past 10 years describing the rationale and outcomes of liver transplantation for children and adults with HoFH. It also provides information on the scale of liver and heart transplantation for a variety of other disorders. SUMMARY: Liver transplantation provides a more effective means of lowering LDL than currently available alternatives such as apheresis and lomitapide but carries with it an unacceptably high risk of posttransplant morbidity and mortality. This is mainly due to the adverse effects of life-long immunosuppressive drug therapy, which restricts the use of liver transplantation to those HoFH patients in whom optimal medical therapy has failed.

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Introduction: Heterozygous pathogenic variants in MYH3 are known to be responsible for distal arthrogryposis. Case report: We report a consanguineous family of four children with two likely pathogenic MYH3 homozygous variants associated with complex movement disorders, especially prominent lingual dystonia, along with skeletal abnormalities. The two variants in MYH3 (c.3445G>A and c.4760T>C) have already been described in patients with congenital arthrogryposis. No other significant variation was found using long-read whole genome sequencing. Discussion: We have extended the phenotype of MYH3-associated arthrogryposis to include movement disorders, which may have been underdiagnosed to date. Highlights: This article extends the phenotype of MYH3-associated arthrogryposis to include movement disorders, illustrating a family of four children presenting MYH3 skeletal disorders and lingual dystonia. Two homozygous likely pathogenic variants have been identified in the four sibs and appear to be causative for both skeletal and neurological phenotypes.

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A 31-year-old male undergoing evaluation for an allogeneic stem cell transplant exhibited a complete mismatch at the MICA locus compared to his biological mother. The recipient was homozygous MICA*008:04, while the mother was homozygous MICA*002:01. Sample mix-up was ruled out and we sought an alternative explanation. Upon investigation of MICA and HLA-B allele linkage, multiple studies reported an association of a MICA deletion (MICAdel) with HLA-B*48. Interestingly, the patient and his mother both typed as HLA-B*48:02. Furthermore, the patient and his mother each typed as MICB*09:01N. Copy number analysis confirmed a single copy of MICA in both samples, thus providing supporting evidence of a MICAdel in both subjects, and consistent with previously published data on the association of a MICAdel with HLA-B*48. What initially appeared to be a maternal exclusion based on a MICA mismatch was instead attributable to a hemizygous loss of MICA. This case highlights two important considerations: 1) evaluating other loci, not generally considered in most clinical matching algorithms can uncover interesting genetic anomalies usually described only in research settings, 2) The appreciation of such findings can lead to studies that explore the clinical impact of such an evolutionary change.

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Atypical teratoid rhabdoid tumors (AT/RT) are characterized by a poor prognosis and a manifestation within the first 2 years of life. Genetic hallmark of these tumors is the homozygous inactivation of SMARCB1 or, in some rare cases, of SMARCA4. While heterozygous pathogenic variants of SMARCA4 have been described, inter alia, in the context of other CNS malignancies such as medulloblastoma or glioblastoma, the co-occurrence of pathogenic variants in both, SMARCB1 and SMARCA4, in the same AT/RT has to our knowledge not been reported previously. Liquid biopsy, a rapidly developing and promising technique measuring cell-free DNA (cfDNA) in body fluids such as the cerebrospinal fluid (CSF), offers a minimally invasive method to assess disease status. It has yet to be established as a standard procedure in the diagnostic workup of CNS tumors. We present the case of a three-year-old male diagnosed with an AT/RT that exhibits both biallelic alterations of SMARCB1 due to a frameshift mutation and loss of heterozygosity as well as a heterozygous missense variant in SMARCA4 presenting with early disease progression. We employed liquid biopsy successfully to monitor disease progression throughout treatment and the subsequent relapse. We highlight the ramifications that simultaneous alterations in two chromatin-modifying genes may have for tumor biology and clinical course.

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Dubin-Johnson syndrome is a rare genetic disease that causes impaired transport of bilirubin. In most cases, there will be no symptoms. However, some people might develop jaundice due to certain conditions. In this case, we would like to present a 54-year-old male patient with Dubin-Johnson syndrome confirmed through genetic analysis showing homozygote mutation of p.Gly693Arg, with no apparent bile deposition in liver biopsy and reactivation of hepatitis B. The Patient had no symptoms since birth and was recently found to have an increased level of direct bilirubin. Further inspection showed a familial pattern of the disease. This is a unique case of homozygote mutation with p.Gly693Arg with atypical presentation of liver biopsy and reactivation of hepatitis B with no clinical manifestation.