Elevated uric acid in gestational diabetes and its risk on pregnancy outcomes.

Background: Over the past few years, gestational diabetes mellitus has become more common. According to earlier research, gestational diabetes mellitus is linked to higher uric acid levels, and gestational hyperuricemia is linked to poor maternal and neonatal outcomes. Aim and objectives: To assess the influence of elevated uric acid >5 mg/dl on pregnancy outcomes such as neonatal weight, respiratory distress, preterm delivery, neonatal intensive care unit admission, premature membrane rupture, oligohydramnios, cesarean section, and intensive care admission for mothers. Setting and methods: It is a prospective cohort study, carried out at obstetric/family medicine outpatient clinics, Cairo University Hospitals on 221 pregnant females with gestational diabetes mellitus in their third trimester of pregnancy, selected by random sampling, performed structured interviews, and tested for serum uric acid level and were separated into two groups, those with elevated uric acid >5 mg/dl (121) and those without elevated uric acid ⩽5 mg/dl (100) patients and then followed up until delivery in Cairo University Hospitals for collecting pregnancy outcome data. Results: There were statistically significant differences between the antepartum uric acid and neonatal complications, maternal complications, preterm, macrosomia, neonatal intensive care unit admission, premature rupture of membranes, oligohydramnios, and cesarean section between both groups. Conclusions: This study showed that elevated serum uric acid >5 mg/dl can predict the incidence of maternal and neonatal problems in gestational diabetes mellitus including preterm, macrosomia, neonatal intensive care unit admission, premature rupture of membranes, oligohydramnios, and cesarean section.

A recurrent KCNK4 variant in a dominant pedigree with hypertrichosis and gingival fibromatosis syndrome: Variable phenotypic expressivity and insights on patients' dental management.

Abnormal hyperpolarization of the KCNK4 gene, expressed in the nervous system, brain, and periodontal ligament fibroblasts, leads to impaired neurotransmitter sensitivity, cardiac arrhythmias, and endocrine dysfunction, as well as, progressive cell proliferation. De novo gain of function variants in the KCNK4 gene were reported to cause a recognizable syndrome characterized by facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth (FHEIG, OMIM# 618381). FHEIG is extremely rare with only three reported cases in the literature. Herein, we describe the first inherited KCNK4 variant (c.730G>C, p.Ala244Pro) in an Egyptian boy and his mother. Variable phenotypic expressivity was noted as the patient presented with the full-blown picture of the syndrome while the mother presented only with hypertrichosis and gingival overgrowth without any neurological manifestations. The c.730G>C (p.Ala244Pro) variant was described before in a single patient and when comparing the phenotype with our patient, a phenotype-genotype correlation seems likely. Atrial fibrillation and joint laxity are new associated findings noted in our patient extending the clinical phenotype of the syndrome. Dental management was offered to the affected boy and a dramatic improvement was noted as the patient regained his smile, restored the mastication function, and resumed his psychological stability.

CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum.

Biallelic variants in CHST3 gene result in congenital dislocation of large joints, club feet, short stature, rhizomelia, kypho-scoliosis, platyspondyly, epiphyseal dysplasia, flared metaphysis, in addition to minor cardiac lesions and hearing loss. Herein, we describe 14 new patients from 11 unrelated Egyptian families with CHST3-related skeletal dysplasia. All patients had spondyloepiphyseal changes that were progressive with age in addition to bifid distal ends of humeri which can be considered a diagnostic key in patients with CHST3 variants. They also shared peculiar facies with broad forehead, broad nasal tip, long philtrum and short neck. Rare unusual associated findings included microdontia, teeth spacing, delayed eruption, prominent angulation of the lumbar-sacral junction and atrial septal defect. Mutational analysis revealed 10 different homozygous CHST3 (NM_004273.5) variants including 7 missense, two frameshift and one nonsense variant. Of them, the c.384_391dup (p.Pro131Argfs*88) was recurrent in two families. Eight of these variants were not described before. Our study presents the largest series of patients with CHST3-related skeletal dysplasia from the same ethnic group. Furthermore, it reinforces that lethal cardiac involvement is a critical clinical finding of the disorder. Therefore, we believe that our study expands the phenotypic and mutational spectrum, and also highlights the importance of performing echocardiography in patients harboring CHST3 variants.

A homozygous loss-of-function variant in BICD2 is associated with lissencephaly and cerebellar hypoplasia.

Developmental brain malformations are rare but are increasingly reported features of BICD2-related disorders. Here, we report a 2-year old boy with microcephaly, profound delay and partial seizures. His brain MRI showed lissencephaly, hypogenesis of corpus callosum, dysplastic hipocampus and cerebellar hypoplasia. Whole-exome sequencing identified a novel homozygous likely pathogenic variant in the BICD2 gene, c.229 C > T p.(Gln77Ter). This is the first report of lissencephaly and cerebellar hypoplasia seen in a patient with homozygous loss-of-function variant in BICD2 that recapitulated the animal model. Our report supports that BICD2 should be considered in the differential diagnosis for patients with lissencephaly and cerebellar hypoplasia Additional clinical features of BICD2 are likely to emerge with the identification of additional patients.

Accuracy of the Traditional COVID-19 Phone Triaging System and Phone Triage-Driven Deep Learning Model.

OBJECTIVES: During the COVID-19 pandemic, a quick and reliable phone-triage system is critical for early care and efficient distribution of hospital resources. The study aimed to assess the accuracy of the traditional phone-triage system and phone triage-driven deep learning model in the prediction of positive COVID-19 patients. SETTING: This is a retrospective study conducted at the family medicine department, Cairo University. METHODS: The study included a dataset of 943 suspected COVID-19 patients from the phone triage during the first wave of the pandemic. The accuracy of the phone triaging system was assessed. PCR-dependent and phone triage-driven deep learning model for automated classifications of natural human responses was conducted. RESULTS: Based on the RT-PCR results, we found that myalgia, fever, and contact with a case with respiratory symptoms had the highest sensitivity among the symptoms/ risk factors that were asked during the phone calls (86.3%, 77.5%, and 75.1%, respectively). While immunodeficiency, smoking, and loss of smell or taste had the highest specificity (96.9%, 83.6%, and 74.0%, respectively). The positive predictive value (PPV) of phone triage was 48.4%. The classification accuracy achieved by the deep learning model was 66%, while the PPV was 70.5%. CONCLUSION: Phone triage and deep learning models are feasible and convenient tools for screening COVID-19 patients. Using the deep learning models for symptoms screening will help to provide the proper medical care as early as possible for those at a higher risk of developing severe illness paving the way for a more efficient allocation of the scanty health resources.

Diagnosis of coronavirus disease 2019 and the potential role of deep learning: insights from the experience of Cairo University Hospitals.

OBJECTIVES: Early detection of coronavirus disease 2019 (COVID-19) is crucial for patients and public health to ensure pandemic control. We aimed to correlate clinical and laboratory data of patients with COVID-19 and their polymerase chain reaction (PCR) results and to assess the accuracy of a deep learning model in diagnosing COVID-19. METHODS: This was a retrospective study using an anonymized dataset of patients with suspected COVID-19. Only patients with a complete dataset were included (n = 440). A deep analytics framework and dual-modal approach for PCR-based classification was used, integrating symptoms and laboratory-based modalities. RESULTS: Participants with loss of smell or taste were two times more likely to have positive PCR results (odds ratio [OR] 1.86). Participants with neutropenia, high serum ferritin, or monocytosis were three, four, and five times more likely to have positive PCR results (OR 2.69, 4.18, 5.42, respectively). The rate of accuracy achieved using the deep learning framework was 78%, with sensitivity of 83.9% and specificity of 71.4%. CONCLUSION: Loss of smell or taste, neutropenia, monocytosis, and high serum ferritin should be routinely assessed with suspected COVID-19 infection. The use of deep learning for diagnosis is a promising tool that can be implemented in the primary care setting.

Confirmation of a Phenotypic Entity for TSPEAR Variants in Egyptian Ectodermal Dysplasia Patients and Role of Ethnicity.

Ectodermal dysplasia (ED) are hereditary disorders characterized by the disturbance of the ectodermal development of at least two of four ectodermal tissues: teeth, hair, nails and sweat glands. Clinical classification of ED is challenged by overlapping features, variable expressivity, and low number of patients, hindering full phenotypic spectrum identification. Disease-causing variants in elements of major developmental pathways, e.g., Ectodysplasin/NFκB, Wnt, and Tp63 pathways, have been identified in fewer than half of ED phenotypes. Whole-exome sequencing (WES) was performed for ten Egyptian ED patients presenting with tooth agenesis, normal sweating, scalp hypotrichosis, and sharing characteristic facial features. WES was followed by in silico analysis of the effects of novel detected genetic variants on mRNA and protein structure. The study identified four novel rare pathogenic and likely pathogenic TSPEAR variants, a gene which was recently found to be involved in ectodermal organogenesis. A novel in-frame deletion recurred in eight patients from six unrelated families. Comparing our cohort to previously reported TSPEAR cohorts highlighted the influence of ethnicity on TSPEAR phenotypic affection. Our study expands the clinical and mutational spectrum of the growing TSPEAR associated phenotypes, and pinpoints the influence of WES and in silico tools on identification of rare disease-causing variants.

OTUD6B-associated intellectual disability: novel variants and genetic exclusion of retinal degeneration as part of a refined phenotype.

Biallelic pathogenic variants of OTUD6B have recently been described to cause intellectual disability (ID) with seizures. Here, we report the clinical and molecular characterization of five additional patients (from two unrelated Egyptian families) with ID due to homozygous OTUD6B variants. In Family I, the two affected brothers had additional retinal degeneration, a symptom not yet reported in OTUD6B-related ID. Whole-exome sequencing (WES) identified a novel nonsense variant in OTUD6B (c.271C>T, p.(Gln91Ter)), but also a nonsense variant in RP1L1 (c.5959C>T, p.(Gln1987Ter)), all in homozygous state. Biallelic pathogenic variants in RP1L1 cause autosomal recessive retinitis pigmentosa type 88 (RP88). Thus, RP1L1 dysfunction likely accounts for the visual phenotype in this family with two simultaneous autosomal recessive disorders. In Family II, targeted sequencing revealed a novel homozygous missense variant (c.767G>T, p.(Gly256Val)), confirming the clinically suspected OTUD6B-related ID. Consistent with the clinical variability in previously reported OTUD6B patients, our patients showed inter- and intrafamilial differences with regard to the clinical and brain imaging findings. Interestingly, various orodental features were present including macrodontia, dental crowding, abnormally shaped teeth, and thick alveolar ridges. Broad distal phalanges (especially the thumbs and halluces) with prominent interphalangeal joints and fetal pads were recognized in all patients and hence considered pathognomonic. Our study extends the spectrum of the OTUD6B-associated phenotype. Retinal degeneration, albeit present in both patients from Family I, was shown to be unrelated to OTUD6B, demonstrating the need for in-depth analysis of WES data in consanguineous families to uncover simultaneous autosomal recessive disorders.

Expansion of the phenotypic and mutational spectrum of Carpenter syndrome.

Carpenter syndrome 1 (CRPT1) is an acrocephalopolysyndactyly (ACPS) disorder characterized by craniosynostosis, polysyndactyly, obesity, and other malformations. It is caused by mutations in the gene RAB23. We are reporting on two patients from two unrelated consanguineous Egyptian families. Patient 1 presented with an atypical clinical presentation of Carpenter syndrome including overgrowth with advanced bone age, epileptogenic changes on electroencephalogram and autistic features. Patient 2 presented with typical clinical features suggestive of Carpenter syndrome. Therefore, Patient 1 was subjected to whole exome sequencing (WES) to find an explanation for his unusual features and Patient 2 was subjected to Sanger sequencing of the coding exons of theRAB23 gene to confirm the diagnosis. We identified a novel homozygous missense RAB23 variant (NM_001278668:c.T416C:p.Leu139Pro) in Patient 1 and a novel homozygous splicing variant (NM_016277.5:c.398+1G > A) in Patient 2. We suggest that the overgrowth with advanced bone age, electroencephalogram epileptogenic changes, and autistic features seen in Patient 1 are an expansion of the Carpenter phenotype and could be due to the novel missense RAB23 variant. Additionally, the novel identified RAB23 variants in Patient 1 and 2 broaden the spectrum of variants associated with Carpenter syndrome.

Expanding the phenotypic and allelic spectrum of SMG8: Clinical observations reveal overlap with SMG9-associated disease trait.

SMG8 (MIM *617315) is a regulatory subunit involved in nonsense-mediated mRNA decay (NMD), a cellular protective pathway that regulates mRNA transcription, transcript stability, and degrades transcripts containing premature stop codons. SMG8 binds SMG9 and SMG1 to form the SMG1C complex and inhibit the kinase activity of SMG1. Biallelic deleterious variants in SMG9 are known to cause a heart and brain malformation syndrome (HBMS; MIM #616920), whereas biallelic deleterious variants in SMG8 were recently described to cause a novel neurodevelopmental disorder (NDD) with dysmorphic facies and cataracts, now defined as Alzahrani-Kuwahara syndrome (ALKUS: MIM #619268). Only eight subjects from four families with ALKUS have been described to date. Through research reanalysis of a nondiagnostic clinical exome, we identified a subject from a fifth unrelated family with a homozygous deleterious variant in SMG8 and features consistent with ALKUS. Interestingly, the subject also had unilateral microphthalmia, a clinical feature that has been described in SMG9-related disorder. Our study expands the phenotypic spectrum of SMG8-related disorder, demonstrates an overlapping phenotype between SMG8- and SMG9-related rare disease traits, provides further evidence for the SMG8 and SMG9 protein interactions, and highlights the importance of revisiting nondiagnostic exome data to identify and affirm emerging novel genes for rare disease traits.

Further Evidence of a Continuum in the Clinical Spectrum of Dominant PIEZO2-Related Disorders and Implications in Cerebellar Anomalies.

Introduction: Pathogenic variants in the PIEZO family member 2 (PIEZO2) gene are known to cause Gordon syndrome (GS), Marden-Walker syndrome (MWS), and distal arthrogryposis type 5 (DA5). Out of these, MWS has a recognizable phenotype that can be discerned easily, but the distinction between GS and DA5 is less evident. Few children with pathogenic PIEZO2 variants have been reported to show posterior fossa anomalies. Methods and Results: By candidate gene targeting guided by proper clinical evaluation and neuroimaging findings, a patient with classic MWS harboring a de novo novel variant (c.8237G>A, p.W2746*) in the C-terminal region of PIEZO2 was identified. In addition, another girl with the typical clinical features of GS is also described carrying the most prevalent reported variant (c.8057G>A, p.R2686H) in PIEZO2. The brain MRI of the 2 patients showed Dandy-Walker malformation (DWM). Diffusion tensor imaging visualized anteroposterior and downward aligned thin middle cerebellar peduncle. The association of DWM with arthrogryposis in the presence of PIEZO2 variants remains quite interesting and provides more evidence that PIEZO2 plays a role in the development of hindbrain although the underlying mechanism remains unclear. Moreover, the 2 girls had distinct foot patterning in the form of shortening of the first and fifth toes. Conclusion: Phenotype analysis and a comprehensive review of the literature strongly support the previously published data and corroborate the evidence that heterozygous PIEZO2-related disorders represent a continuum with overlapping phenotypic features.

Gene Mutations of the Three Ectodysplasin Pathway Key Players (EDA, EDAR, and EDARADD) Account for More than 60% of Egyptian Ectodermal Dysplasia: A Report of Seven Novel Mutations.

Ectodermal dysplasia (ED) is a diverse group of genetic disorders caused by congenital defects of two or more ectodermal-derived body structures, namely, hair, teeth, nails, and some glands, e.g., sweat glands. Molecular pathogenesis of ED involves mutations of genes encoding key proteins of major developmental pathways, including ectodysplasin (EDA) and wingless-type (WNT) pathways. The most common ED phenotype is hypohidrotic/anhidrotic ectodermal dysplasia (HED) featuring hypotrichosis, hypohidrosis/anhidrosis, and hypodontia. Molecular diagnosis is fundamental for disease management and emerging treatments. We used targeted next generation sequencing to study EDA, EDAR, EDARADD, and WNT10A genes in 45 Egyptian ED patients with or without hypohidrosis. We present genotype and phenotype data of 28 molecularly-characterized patients demonstrating genetic heterogeneity, variable expressivity, and intrafamilial phenotypic variability. Thirteen mutations were reported, including four novel EDA mutations, two novel EDARADD, and one novel EDAR mutations. Identified mutations congregated in exons encoding key functional domains. EDA is the most common gene contributing to 85% of the identified Egyptian ED genetic spectrum, followed by EDARADD (10%) and EDAR (5%). Our cohort represents the first and largest cohort from North Africa where more than 60% of ED patients were identified emphasizing the need for exome sequencing to explore unidentified cases.

An Adapted Online Family Medicine Training for House Officers Amid Covid-19 Pandemic in Egypt.

INTRODUCTION: The COVID-19 pandemic is an unprecedented challenge to house officers training programs because of the safety measures. OBJECTIVE: This current study aimed to introduce the adaptation of family medicine training for house officers during COVID-19 pandemic and gauge their level of satisfaction with the training. METHODS: Unfortunately, more than one-fourth of the house officers attending the family medicine training turned out to be hospital-admitted or in obligatory home isolation. A time-sensitive plan was proposed to maintain a competent training guaranteeing safety and support of house officers and fulfilling the training objectives in a virtual setting. Three mentors were assigned to each 10 house officers to provide continuous support and monitoring. Tutor and house officer interaction and reflection were maintained through a virtual clinical training session via Zoom application and a daily online discussion of a clinical scenario. Peer interaction was provided through post-webinar and small-group online discussion sessions. RESULTS: The adapted training was applied on thirteen cohorts of house officers. The response rate was 70% (666 out of 950). Most of them were satisfied with the training (84.6%). Their satisfaction with each modality of the training was encouraging. CONCLUSIONS: During COVID-19 pandemic, successful adaptation of family medicine training has succeeded in fulfilling the training objectives and providing psychological support and engagement for house officers without burdening the hospital-admitted and home-isolated house officers.

Effect of DASH Diet Versus Healthy Dietary Advice on the Estimated Atherosclerotic Cardiovascular Disease Risk.

INTRODUCTION: Cardiovascular disease (CVD) is the most leading cause of mortality worldwide. Changes in diet can reduce subclinical cardiac injury and inflammation in parallel with reductions of other CVD risk factors. AIM: The study aimed to evaluate the beneficial effect of the DASH diet versus usual healthy dietary advice (HDA) on the estimated risk of atherosclerotic cardiovascular disease (ASCVD). METHODS: It was a prospective interventional nonrandomized controlled study, conducted on 92 participants attending Family Medicine Outpatient Clinics, Cairo University. The participants were assigned to 2 dietary groups, the DASH and HDA groups, for 12 weeks. All subjects were subjected to anthropometric measurement, assessment of lipid profile, and the estimated cardiovascular risk pre-and post-intervention. RESULTS: The estimated cardiovascular risk was reduced significantly in both the DASH and HDA groups, with no statistically significant difference between the 2 groups regarding the risk reduction. By comparing the percent change between pre and post-intervention in both DASH and HDA groups, the following are the results: BMI dropped by 6.5% versus 2.5%, systolic blood pressure decreased by 6.9% and 4.1%, fasting blood sugar dropped by 5.5% and 3.1%, total cholesterol dropped by 5.2% and 3.1%, LDL dropped by 8.2%, and 3.1%, and HDL increased by 8.2% and 2.4%, in DASH and HDA groups, respectively. CONCLUSION: Both the DASH diet and HDA are associated with improvement in CVD risk factors. Although better risk factors decline with the DASH diet, there was no statistically significant difference between the 2 groups.

Microcephalic osteodysplastic primordial dwarfism type II: Additional nine patients with implications on phenotype and genotype correlation.

PCNT encodes a large coiled- protein localizing to pericentriolar material and is associated with microcephalic osteodysplastic primordial dwarfism type II syndrome (MOPD II). We report our experience of nine new patients from seven unrelated consanguineous Egyptian families with the distinctive clinical features of MOPD II in whom a customized NGS panel showed homozygous truncating variants of PCNT. The NGS panel results were validated thereafter using Sanger sequencing revealing three previously reported and three novel PCNT pathogenic variants. The core phenotype appeared homogeneous to what had been reported before although patients differed in the severity showing inter and intra familial variability. The orodental pattern showed atrophic alveolar ridge (five patients), rootless tooth (four patients), tooth agenesis (three patients), and malformed tooth (three patients). In addition, mesiodens was a novel finding found in one patient. The novel c.9394-1G>T variant was found in two sibs who had tooth agenesis. CNS anomalies with possible vascular sequelae were documented in two male patients (22.2%). Simplified gyral pattern with poor development of the frontal horns of lateral ventricles was seen in four patients and mild thinning of the corpus callosum in two patients. Unilateral coronal craniosynstosis was noted in one patient and thick but short corpus callosum was an unusual finding noted in another. The later has not been reported before. Our results refine the clinical, neuroradiological, and orodental features and expand the molecular spectrum of MOPD II.

KBG syndrome in two patients from Egypt.

KBG syndrome is an intellectual disability (ID) associated with multiple congenital anomalies in which the macrodontia could be the clue for the diagnosis. It is caused either by heterozygous variant in ANKRD11 gene or 16q24.3 microdeletions that involve the ANKRD11 gene. Here, we report on two unrelated male patients who presented with ID, short stature, webbing of neck, and cryptorchidism. Noonan syndrome was suspected first but the presence of macrodontia in both patients pointed to KBG syndrome which was confirmed thereafter by the identification of a novel pathogenic variant in ANKRD11 gene, c.5488G>T (p.E1830*). Macrodontia was noticed in all the deciduous anterior teeth in Patient 1. This observation was reported previously in few patients, but it seems to be a common feature that could be misdiagnosed as premature eruption of teeth. Therefore, our results confirm that maxillary permanent central incisors may not be the only teeth affected in KBG but also all the deciduous teeth. Interestingly, desquamative gingivitis was additionally noted in Patient 1, which has not been reported previously, however; it could be a coincidental finding. To the best of our knowledge, this is the first report from Egypt.

Perceived Stress Scale Among Adolescents with Polycystic Ovary Syndrome.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common disorder that affects women during their reproductive age. Previous studies have suggested that PCOS may be linked to some mental disorders. AIM: The study aimed to estimate the perceived stress among adolescents with PCOS and investigate the relationship between PCOS symptoms and perceived stress scale (PSS) in adolescents. METHODS: This was a case control study with 72 participants (between 11 and 19 years); 36 adolescents with PCOS and 36 matched controls were recruited from family medicine and gynecological outpatient clinics at Cairo University hospitals. They participated in a structured interview using a pre-designed questionnaire. Full general examination was conducted, including anthropometric measures, acne staging, and hirsutism staging using the Ferriman-Gallwey score. We assessed the severity of stress over the previous month of interview using the 10-item perceived stress scale (PSS-10). RESULTS: There was a statistically significant difference in PSS scores among adolescents with and without PCOS; most cases with severe PSS scores were found to have PCOS. The mean score of PSS was higher in PCOS adolescents (20.416) than in the non-PCOS control group (18.8), but with no statistical significance. There was no significant correlation between the severity of PSS in PCOS adolescents and BMI, WC, acne or hirsutism severity; there was only weak positive correlation between PSS score and DBP (r=0.167). CONCLUSION: PCOS adolescents have higher incidence of severe perceived stress; however, degree of PSS was independent of BMI, WC, acne or hirsutism severity and shows only weak correlations with DBP. Our results urge the need for implementing a holistic approach that should include stress reduction programs to help adolescents get ready for their adult life.

Bilateral Calcification of Basal Ganglia in a Patient with Duplication of Both 11q13.1q22.1 and 4q35.2 with New Phenotypic Features.

We report on a female patient who presented with severe intellectual disability and autistic behavior, dysmorphic features, orodental anomalies, and bilateral calcification of basal ganglia. Using a high-density oligonucleotide microarray, we have identified a de novo duplication of 11q13.1q22.1 involving the dosage sensitive genes FGF3 and FGF4, genes related to autosomal dominant disorders KMT5B, GAL, SPTBN2, and LRP5, susceptibility loci SCZD2, SLEH1, and SHANK2, mitochondrial genes NDUFV1, NDUFS8, and TMEM126B, and many loss of function genes, including PHOX2A, CLPB, MED17, B3GNT1, LIPT2, and CLPB. However, the duplication did not involve Ribonuclease H2, subunit C (RNASEH2C) which is considered to be located in the critical region for Aicardi-Goutières syndrome. In combination with the duplication at 11q13.1, a 1.849-Mb heterozygous duplication at 4q35.2 was also identified. Although this duplicated region does not contain causative genes related to brain calcification, the duplication at 4q35 was reported previously in a patient with basal ganglia calcification, coats' like retinopathy, and glomerulosclerosis. Our patient's presentation and genomic findings indicate that duplication of 4q35.2 could be a novel genetic cause of calcification of basal ganglia. Our report also underscores the clinical significance of rearrangements in 11q13.1q22.1 in the pathogenesis of basal ganglia calcification.

PUS7 mutations impair pseudouridylation in humans and cause intellectual disability and microcephaly.

Pseudouridylation is the most common post-transcriptional modification, wherein uridine is isomerized into 5-ribosyluracil (pseudouridine, Ψ). The resulting increase in base stacking and creation of additional hydrogen bonds are thought to enhance RNA stability. Pseudouridine synthases are encoded in humans by 13 genes, two of which are linked to Mendelian diseases: PUS1 and PUS3. Very recently, PUS7 mutations were reported to cause intellectual disability with growth retardation. We describe two families in which two different homozygous PUS7 mutations (missense and frameshift deletion) segregate with a phenotype comprising intellectual disability and progressive microcephaly. Short stature and hearing loss were variable in these patients. Functional characterization of the two mutations confirmed that both result in decreased levels of Ψ13 in tRNAs. Furthermore, the missense variant of the S. cerevisiae ortholog failed to complement the growth defect of S. cerevisiae pus7Δ trm8Δ mutants. Our results confirm that PUS7 is a bona fide Mendelian disease gene and expand the list of human diseases caused by impaired pseudouridylation.

Phenotypic and molecular insights into PQBP1-related intellectual disability.

We report two discordant clinical and imaging features in four male patients from two unrelated families of Egyptian descent with hemizygous pathogenic variants in PQBP1. The three patients of the first family displayed the typical features underlying PQBP1 such as the long triangular face, bulbous nose, hypoplastic malar region, and micrognathia, which were subsequently confirmed using targeted sequence analysis that showed a previously reported nonsense mutation c.586C>T p.R196*. Whole exome sequencing identified a novel missense PQBP1 variant c.530G>A:p.R177H in the second family, in which the index patient presented with intellectual disability and dysmorphic facial features reminiscent of Kabuki-like syndrome and his brain magnetic resonance imaging revealed partial agenesis of corpus callosum, mild vermis, and brainstem hypoplasia. These imaging features are distinct from the previously described with a well-known phenotype that is already known for PQBP1. This report expands the phenotypic spectrum of PQBP1-related disorders and is the second reported missense PQBP1 variant. Further, it highlights the possible role of PQBP1 in hindbrain development.