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Fetal brain arrest is an extremely rare genetic disorder that was described in few patients and encompasses very unique findings of underdeveloped cerebral hemispheres in association with collapsed skull bones. Based on the recurrence among sibs, an autosomal recessive mode of inheritance was proposed; however, no causative gene was identified so far. Here, we report the identification of biallelic variants in the WDR81 gene in two unrelated families (4 patients) with fetal brain arrest including the originally described family and an additional new family. Two homozygous variants were identified: a new missense (c.1157 T > C, p.Val386Ala) and a previously described frameshift variant, c.4668_4669delAG (p.Gly1557AspfsTer16). We assessed the expression of WDR81 at the protein level by western blot analysis using primary skin fibroblast cultures established from the patient with the missense variant and noticed that WDR81 expression was significantly reduced in comparison to normal control confirming the pathogenicity of this variant. Our findings confirm the involvement of WDR81 in the pathogenesis of fetal brain arrest syndrome and suggest that fetal brain arrest represents the severe end of the spectrum phenotypes caused by pathogenic variants in WDR81. In addition, we reviewed the clinical and molecular data on WDR81-related disorders and phenotype/genotype correlations.

Micro and Martsolf syndromes are rare clinically and genetically overlapping disorders caused by mutations in RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20 genes. We describe 34 new patients, 27 with Micro and 7 with Martsolf. Patients presented with the characteristic clinical manifestations of the two syndromes including postnatal microcephaly, congenital cataracts, microphthalmia, optic atrophy, spasticity and intellectual disability. Brain imaging showed in the majority of cases polymicrogyria, thin corpus callosum, cortical atrophy, and white matter dysmyelination. Unusual additional findings were pectus excavatum (4 patients), pectus carinatum (3 patients), congenital heart disease (3 patients) and bilateral calcification in basal ganglia (1 patient). Mutational analysis of RAB3GAP1 and RAB3GAP2 revealed 21 mutations including 14 novel variants. RAB3GAP1 mutations were identified in 22 patients with Micro including a deletion of the entire gene in one patient. On the other hand, RAB3GAP2 mutations were identified in two patients with Micro and all Martsolf patients. Moreover, exome sequencing unraveled a TBC1D20 mutation in an additional family with Micro syndrome. Our results expand the phenotypic and mutational spectrum associated with Micro and Martsolf syndromes. Due to the overlapped severities and genetic basis of both syndromes, we suggest to be comprehended as one entity "Micro/Martsolf spectrum" or "RAB18 deficiency". This article is protected by copyright. All rights reserved.

Bruck Syndrome (BS) is a very rare disorder characterized by osteogenesis imperfecta (OI) associated with congenital contractures and is caused by mutations in FKBP10 or PLOD2 genes. Herein, we describe 13 patients from 9 unrelated Egyptian families with BS. All patients had white sclerae, recurrent fractures, kyphoscoliosis and osteoporosis with variable degrees of severity. Large joint contractures were seen in 11 patients, one patient had contractures of small interphalangeal joints, and one patient had no contractures. Unusual findings noted in individual patients included microcephaly, dental malocclusion, enamel hypoplasia, unilateral congenital dislocation of knee joint, prominent tailbone, and myopathy. Nine different variants were identified in FKBP10 and PLOD2 including five novel ones. FKBP10 variants were found in six families (67%) while PLOD2 variants were identified in three families (33%). The four families, with two affected sibs each, showed inter- and intrafamilial phenotypic variability. In conclusion, we report five novel variants in FKBP10 and PLOD2 thus, expanding the mutational spectrum of BS. In addition, our results expand the phenotypic spectrum, describe newly associated orodental findings, and further illustrate the phenotypic overlap between OI and Bruck syndrome supporting the suggestion of considering BS as a variant of OI rather than a separate entity.

This study describes the clinical, radiological, and molecular data of four new patients with osteoporosis-pseudoglioma syndrome and assesses their response to bisphosphonate therapy.Osteoporosis-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).We 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.All 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.Our 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.

Sjögren-Larsson syndrome (SLS) is a rare neurocutaneous disorder characterized by congenital ichthyosis, spastic diplegia and intellectual disability. It is an inborn error of lipid metabolism caused by biallelic mutations in the ALDH3A2 gene encoding the fatty aldehyde dehydrogenase that plays a pivotal role in metabolism of long-chain aliphatic aldehydes and alcohols. In this report, we describe the clinical, neuro-radiological and molecular findings of 35 patients with SLS. All patients shared the typical clinical manifestations of SLS including spasticity, ichthyosis and intellectual disability. Brain MRI demonstrated deep while matter affection in all patients that varied in severity. Mutational analysis of the ALDH3A2 gene revealed 16 distinct mutations including 11 previously unreported ones. Three mutations (p.S365L, p.R9* and p.G400R) were recurrent in our patients with frequencies ranging from 12 to 24%. Interestingly, patients carrying the two new mutations p.R9* and p.G400R shared similar haplotypes suggesting possible founder effects in our population. In conclusion, we present a large cohort of patients from the same ethnicity with the characteristic clinical and brain imaging findings of SLS but with variable inter and intra familial severity and expressivity. We also identified many novel and founder ALDH3A2 mutations thus expanding the mutational spectrum of the disorder.

Fetal brain arrest is an extremely rare genetic disorder that was described in few patients and encompasses very unique findings of underdeveloped cerebral hemispheres in association with collapsed skull bones. Based on the recurrence among sibs, an autosomal recessive mode of inheritance was proposed; however, no causative gene was identified so far. Here, we report the identification of biallelic variants in the WDR81 gene in two unrelated families (4 patients) with fetal brain arrest including the originally described family and an additional new family. Two homozygous variants were identified: a new missense (c.1157 T C, p.Val386Ala) and a previously described frameshift variant, c.4668_4669delAG (p.Gly1557AspfsTer16). We assessed the expression of WDR81 at the protein level by western blot analysis using primary skin fibroblast cultures established from the patient with the missense variant and noticed that WDR81 expression was significantly reduced in comparison to normal control confirming the pathogenicity of this variant. Our findings confirm the involvement of WDR81 in the pathogenesis of fetal brain arrest syndrome and suggest that fetal brain arrest represents the severe end of the spectrum phenotypes caused by pathogenic variants in WDR81. In addition, we reviewed the clinical and molecular data on WDR81-related disorders and phenotype/genotype correlations.

Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and "major spliceosome-opathies" as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.

Background Hyperphosphatasia with mental retardation syndrome (HPMRS) is caused by recessive mutations in genes involved in the glycosylphosphatidylinsitol pathway, including PGAP3. Materials and Methods We describe 10 patients from 8 Egyptian families presenting with developmental delay, severe intellectual disability, distinct facial dysmorphism and increased alkaline phosphatase. Sanger sequencing of PGAP3 was performed. Results Eight patients had cleft palate, 4 had postnatal microcephaly and 5 had seizures. Neuro-imaging findings showed thin corpus callosum in 9 patients, mild ventriculomegaly in 3 patients and variable degrees of cerebellar vermis hypoplasia in 4 patients, a finding not previously reported in patients with HPMRS. Additional manifestations included double row teeth, hypogenitalism and congenital heart disease. Biallelic loss of function mutations in the PGAP3 gene were detected in all patients. Nine patients were homozygous for the c.402dupC (p.M135Hfs*28) mutation strongly suggesting a founder effect. On the other hand, 1 patient had a novel mutation, c.817_820delGACT (p.D273Sfs*37). Conclusion This is the largest series of patients with HPMRS from same ethnic group. Our results reinforce the distinct clinical and facial features of PGAP3-related HPMRS which are the clue for targeted genetic testing. Moreover, we present additional unreported clinical and neuro-imaging findings and a novel mutation thus expanding the phenotypic and mutational spectrum of this rare disorder.

Objective The purpose of this study was to elucidate the facial morphology and the pattern of internal malformations in three fetuses with RS born to first cousins of Egyptian decent. Methods The fetal ultrasonography findings were highly suggestive of RS leading to targeted Sanger sequencing of FAM20C and postnatal assessment. Results The prenatal ultrasound findings of osteosclerotic skull, exorbitism, hypoplastic nose, midface hypoplasia, small mouth with down-curved corners, and a distinct and recognizable pattern of intracranial calcification were identified in three fetuses with RS. The calcifications were evident specifically around the corpus callosum and/or ventricular walls. Ectopic renal and hepatic calcifications, pulmonary hypoplasia, mild rhizomelic shortening of the upper limbs, intrauterine fractures, and cerebellar hypoplasia were also noted. Molecular analysis identified three novel homozygous variants, two frameshift: [c.456delC (p.Gly153Alafs*34)] in exon 1 and [c.905delT (Phe302Serfs*35)] in exon 4 and one nonsense mutation in exon 10, [c.1557C>G(p.Tyrs519*)]. The three variants were segregated with the phenotype. This is the first description of a phenotype associated with homozygous truncating variants of FAM20C. Conclusion RS has characteristic prenatal ultrasound findings which can improve the prenatal identification of this condition and help in guiding the molecular diagnosis and counseling.

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.

Aicardi-Goutieres syndrome (AGS) is one of the expanding group of inherited congenital infection like syndromes. Here, we describe the detailed clinical and imaging findings of two sibs with AGS. Each shows scattered periventricular intracranial calcifications, severe global delay, seizures, microcephaly and spasticity. Interestingly, chilblains were observed in the two sisters as well as their parents and a paternal uncle. The brain MRI of the older sister showed marked ventricular dilatation as a result of unusual associated porencephalic cysts. Unexpectedly, unilateral cerebellar hypoplasia was also noted. In comparison, her younger sister displayed the classic atrophic changes and white matter loss of AGS. The diagnosis of AGS was confirmed by sequence analysis, which identified a previously reported homozygous RNASEH2B mutation, c.554 T > G (p.V185G). Parents were heterozygous for the same mutation. Further molecular analysis excluded mutations in potentially related manifestations of COL4A1 gene. This is the first report of chilblains associated with heterozygous RNASEH2B mutation. Further, the brain imaging findings appear particularly interesting, which until now has not been reported in any AGS patient. We discuss the possible reasons for this unusual presentation.