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Pontocerebellar hypoplasia (PCH) is a rare heterogeneous neurodegenerative disorder affecting the pons and cerebellum and is currently classified into 17 types (PCH1-PCH17). PCH1 is distinguishable from other types by the association of spinal motor neuron dysfunction. Based on the underlying genetic etiology, PCH1 is further classified into 6 different subtypes (PCH1 A-F). Of them, PCH type 1C is caused by pathogenic variants in EXOSC8 gene and so far, only four families have been described in the literature. In this study, we report a new patient with PCH1 who proved by whole-exome sequencing to harbor a novel homozygous missense variant in the splice region of EXOSC8 gene (c.238 G > A; p.Val80Ile). Studying mRNA of the patient confirmed that this variant results in skipping of exon 5 of the gene and early protein truncation. Our patient presented with the main clinical findings of PCH type 1C including psychomotor retardation, spasticity, spinal muscle atrophy, and respiratory problems. However, unlike most of the reported cases, he did not develop hearing or visual impairment and displayed a longer survival. In addition, our patient had dysmorphic facies, nystagmus, congenital esotropia and contractures which were infrequently described in patients with EXOSC8 . Diaphragmatic hernia, dilated lateral ventricles, hypoplastic temporal lobes, and thinning of the brain stem were additional new findings noted in our patient. This study presents the fifth family with this extremely rare type of PCH and expands the associated clinical and brain imaging findings.

Biallelic pathogenic variants in MADD lead to a very rare neurodevelopmental disorder which is phenotypically pleiotropic grossly ranging from severe neonatal hypotonia, failure to thrive, multiple organ dysfunction, and early lethality to a similar but milder phenotype with better survival. Here, we report 5 patients from 3 unrelated Egyptian families in whom 4 patients showed the severe end of the spectrum displaying neonatal respiratory distress, hypotonia and chronic diarrhea while one patient presented with the mild form displaying moderate intellectual disability and myopathy. In addition, we observed distal arthrogryposis and nonspecific structural brain anomalies in all our patients. Interestingly, cerebellar and brainstem hypoplasia were noted in one patient. Whole exome sequencing identified three novel homozygous variants in the MADD gene: two likely pathogenic [c.4321delC p.(Gln1441ArgfsTer46) and c.2620 C > T p.(Arg874Ter)] and one variant of uncertain significance (c.4307 G > A, p.Arg1436Gln). The variants segregated with the disease in all available family members. Our findings confirm that arthrogryposis, genital, cardiac and structural brain anomalies are manifestations of MADD which expand the spectrum of MADD -related neurodevelopmental disorder. Moreover, they further highlight the convergence of MADD variants on different organ systems leading to complex phenotypes.

SummaryThis study describes the clinical, radiological, and molecular data of four new patients with osteoporosis-pseudoglioma syndrome and assesses their response to bisphosphonate therapy.IntroductionOsteoporosis-pseudoglioma syndrome (OPPG) is a very rare disorder characterized mainly by severe juvenile osteoporosis and congenital blindness. OPPG is caused by biallelic mutations in the gene encoding low-density lipoprotein receptor-related protein 5 (LRP5). MethodsWe present the clinical, radiological, and molecular findings of four new patients with OPPG from Egypt. We also assessed patients’ response to oral and intravenous bisphosphonate therapy. ResultsAll patients had reduced bone mineral density (BMD) with variable number of fractures per year, in addition to bone abnormalities and the characteristic eye phenotype associated with OPPG. Mutation analyses of LRP5 gene revealed three different homozygous variants including two novel ones, c.7delG (p.A3Qfs*80) and c.3280G > A (p.E1094K). The c.3280G > A (p.E1094K) was recurrent in two unrelated patients who shared a unique haplotype suggesting a possible founder effect. The use of bisphosphonate therapy was beneficial; however, intravenous bisphosphonate administration led to a more favorable response. ConclusionOur study described the phenotypic and genetic features of four patients with OPPG and identified two new LRP5 variants, thus expanding the mutational spectrum of OPPG. In addition, our study reinforces the efficiency of using intravenous bisphosphonates in the management of patients with OPPG.

Odontochondrodysplasia (ODCD) is a rare skeletal dysplasia characterized by short stature, skeletal deformities, and dentinogenesis imperfecta (DI). Although the majority of cases were associated with biallelic variants in TRIP11 , one study described a homozygous truncating variant in MIA3 , encoding TANGO1, in four sibs with ODCD in association with insulin-dependent diabetes, hearing loss, obesity, and intellectual disability. Subsequently, a homozygous truncating variant in the luminal domain of TANGO1 was identified in a fetus with a lethal skeletal dysplasia and fetal hydrops. Herein, we describe two unrelated patients with a distinct phenotype including severe short limbs, short stature, metaphyseal dysplasia, dysmorphic facies, lax joints, and DI. Other variable features were scoliosis, squint, and cardiac problems. Exome sequencing revealed two homozygous MIA3 variants in the luminal domain of TANGO1, c.354+2T>G and p.Cys38Phe. The c.354+2T>G variant was confirmed by investigating the patient’s mRNA to result in exon 3 skipping and an inframe deletion of 29 amino acids. Our patients lacked the extra-skeletal manifestations noted in the four sibs with MIA3 variant. However, they had more severe skeletal deformities closely resembling those observed in patients with TRIP11 variants. Our study suggests the presence of a phenotypic spectrum associated with MIA3 variants including ODCD with milder skeletal deformities, a classic ODCD with severe skeletal deformities, and a lethal skeletal dysplasia at the severe end of the spectrum. Although the striking phenotypic variability appears to be related to the type and or the location of the MIA3 variants, the influence of other factors cannot be ruled out.

Biallelic variants in the adenosine deaminase tRNA specific 3 (ADAT3) gene are associated with a distinct neurodevelopmental disorder characterized by dysmorphic facies, poor growth, cognitive impairment, and variable brain anomalies. We describe 24 patients from 16 unrelated Egyptian families with ADAT3 -related neurodevelopmental disorder. All patients presented with developmental delay, growth retardation, cognitive impairment, and the characteristic facial features of the disorder, which appears to be more recognizable in older patients. Seizures were noted in 20% of patients and showed favorable responses to treatment. Brain imaging showed corpus callosum abnormalities in most patients (91.6%), followed by delayed myelination and cortical atrophy. Exome sequencing identified three ADAT3 variants, including the Saudi founder variant c.430G > A (p.Val144Met), which was detected in 17 patients (70%). In addition, two novel variants were identified, c.319G > A (p.Glu107Lys) and c.1013_1018dup (p.Arg338_Ile339dup). The c.319G > A (p.Glu107Lys) was recurrent in 6 patients (25%) who shared a similar haplotype, suggesting a likely founder effect in our population. On the other hand, the c.1013_1018dup (p.Arg338_Ile339dup) was identified in a single patient. Our study reports a large cohort of patients with ADAT3 -related neurodevelopmental disorder from Egypt and reinforces the clinical and brain imaging characteristics of the disorder. The high prevalence of the c.430G > A (p.Val144Met) in our population strongly suggests the existence of a founder effect of this variant in the Middle East and Arab region. In addition, we report a new founder variant expanding the mutational spectrum of this rare disorder.

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.

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.

Background Leukodystrophies (LDs) and genetic leukoencephalopathies (GLEs) encompass the spectrum of genetic white matter disorders (GWMDs). Despite their clinical significance, limited studies have investigated GWMDs in Egypt. Therefore, this study aimed to characterize pediatric patients diagnosed with GWMDs in the Beni-Suef Governorate, Upper Egypt. Methods We reviewed the records of patients diagnosed with GWMDs who presented over five years to the pediatric neurology clinic of a tertiary care hospital in Beni-Suef Governorate, Upper Egypt. The study included 142 patients aged < 18 years diagnosed with GWMD confirmed by brain imaging, metabolic, and/or molecular genetic testing. Patients were classified as LDs or GLEs per the 2015 Global Leukodystrophy Initiative Consortium (GLIA) criteria. Results Fifty-six cases were identified to have LDs, while 86 were classified as GLEs. Metachromatic leukodystrophy (MLD) was the most common LD (13 patients), followed by megalencephalic leukoencephalopathy with subcortical cysts (MLC) (10 patients). The most common GLEs were lysosomal storage disorders (LSDs) (22 patients,) followed by Cockayne syndrome (11 patients), along with other miscellaneous disorders. The cumulative incidence of GWMDs in children under 18 was estimated at 10.8 cases per 100,000 population during the five-year study period. Thirty-one novel variants were identified, comprising 10 for LDs and 21 for GLEs. The mortality rate was 39.3% and 22.1% among patients with LDs and GLEs, respectively. Conclusions This study presents the first cohort of GWMDs reported from the Beni-Suef Governorate, Upper Egypt. The study provides significant data regarding regional etiological patterns, clinical trajectories, and molecular profiles. Additionally, the study findings provide a foundational framework for establishing a national GWMD registry and inform future diagnostic and therapeutic strategies.

WLS (Wnt ligand secretion mediator or Wntless) orchestrates the secretion of all Wnt proteins, a family of evolutionary conserved proteins, involved in Wnt signaling pathway that has many essential biological functions including the regulation of development, cell proliferation, migration and apoptosis. Biallelic variants in WLS have recently been described in 10 patients with pleiotropic multiple congenital anomalies (MCA) known as Zaki syndrome. We identified a likely disease-causing variant in WLS (c.1579G>A, p.Gly527Arg) in a boy presented with a broad range of MCA including microcephaly, facial dysmorphism, alopecia, ophthalmologic anomalies, and complete soft tissue syndactyly. These features were reminiscent of Zaki syndrome although variable clinical severity was observed. In a detailed clinical assessment, our patient also displayed microphthalmia, dental anomalies, skeletal dysplasia with spontaneous fractures and Dandy-Walker malformation. As such, we extend the phenotype linked to Zaki syndrome. This study further highlights the importance of a thorough clinical evaluation to delineate the phenotypic spectrum associated with WLS variants and suggests that genotype-phenotype correlations due to variant localization seems likely. However, future work on additional patients and more functional studies may give further insights into genotype-phenotype correlations and the complex function of WLS.

Aim This study aimed to assess neonatal sensorineural hearing loss (SNHL) in newborns in Menoufia Governorate, Egypt, who underwent an extended hearing loss screening program, focusing on prevalence, types, and genetic analysis. Patients and methods This study was conducted on 3500 Egyptian newborn infants who came to the family health care units in Menoufia Governorate for routine neonatal hearing screening tests, including 1st and 2nd otoacoustic emissions (OAE). A diagnostic auditory brainstem response (ABR) test was performed on the neonates who failed to pass the 2nd OAE screening test with a REFER result. Whole exome sequencing (WES) was performed on the neonates with sensorineural hearing loss (SNHL). Results The referral rate after the first time OAE was 5.1%, while after the second time, it was 0.4%. Most referred cases were bilaterally affected in both tests. Due to otitis media with effusion, conductive hearing loss was detected in 6 neonates (0.17%). Sensorineural hearing loss was identified in two newborns (0.05%). WES revealed a homozygous pathogenic variant in the SLC26A4 gene (c.1198delT: p.Cys400ValfsTer32) in one neonate and a homozygous variant of uncertain significance in the MYO5C gene (c.1322C>T: p.Thr441Ile) in the other one. Conclusion Sensorineural hearing loss constitutes 0.05% of the Egyptian neonates in Menoufia Governorate. Genetic variants in the SLC26A4 and MYO5C genes represent the possible genetic causes of SNHL in the two affected newborns.