Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications.

PPFIBP1 encodes for the liprin-ß1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications.

New insights into the clinical and molecular spectrum of the MADD-related neurodevelopmental disorder.

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.

Novel homozygous ESAM variants in two families with perinatal strokes showing variable neuroradiologic and clinical findings.

Biallelic loss of function variants in ESAM (endothelial cell adhesion molecule) have recently been reported in 14 individuals (9 families) presenting with prenatal intracranial hemorrhage. Here, we describe four patients from two unrelated families in whom three of them presented with variable onset encephalopathy and seizures while one only displayed profound delay without seizures. Brain MRI showed variable onset intracranial hemorrhage that evolved to hydrocephalus in 3 patients, whereas hemosiderin deposits, white matter volume loss, and porencephalic cysts were noted in one patient. Unlike the majority of described cases, the youngest brother of the first family did not show microcephaly and failure to thrive. Exome sequencing identified two novel homozygous ESAM variants. A splice variant (c.731-2A>G) was identified in one family which was confirmed by investigating the patient's mRNA to result in exon skipping and early protein truncation. In addition, a missense variant (c.561G>C; p.Trp187Cys) was identified in the other family, which is the first disease causing missense variant to be described in patients with ESAM deficient phenotype. In addition, a maternally inherited pathogenic MC4R variant (c.811T>C; p.Cys271 Arg) was also identified in the youngest brother of the first family. Variants in the MC4R gene are associated with a non-syndromic form of obesity that could explain the unusual macrocephaly and obesity. Our work establishes ESAM as a tight junction gene that can present with variable neuroradiological and clinical phenotypes when mutated. Moreover, it refines the phenotype of this ultrarare syndrome and extends the number and type of variants described to date.

Delineating the phenotype of PNPLA8-related mitochondriopathies.

Pathogenic variants in PNPLA8 have been described either with congenital onset displaying congenital microcephaly, early onset epileptic encephalopathy and early lethality or childhood neurodegeneration with progressive microcephaly. Moreover, a phenotype comprising adulthood onset cerebellar ataxia and peripheral neuropathy was also reported. To our knowledge, only six patients with biallelic variants in PNPLA8 have been reported so far. Here, we report the clinical and molecular characterizations of three additional patients in whom exome sequencing identified a loss of function variant (c.1231C>T, p.Arg411Ter) in Family I and a missense variant (c.1559T>A, p.Val520Asp) in Family II in PNPLA8. Patient 1 presented with the congenital form of the disease while Patients 2 and 3 showed progressive microcephaly, infantile onset seizures, progressive cortical atrophy, white matter loss, bilateral degeneration of basal ganglia, and cystic encephalomalacia. Therefore, our results add the infantile onset as a new distinct phenotype of the disease and suggest that the site of the variant rather than its type is strongly correlated with the disease onset. In addition, these conditions demonstrate some overlapping features representing a spectrum with clinical features always aligning with different age of onset.

Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities.

PURPOSE: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder. METHODS: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature. RESULTS: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss. CONCLUSION: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities.

Expanding the phenotypic spectrum and clinical severity associated with WLS gene.

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.

A founder PPIL1 variant underlies a recognizable form of microlissencephaly with pontocerebellar hypoplasia.

Biallelic variants in PPIL1 have been recently found to cause a very rare type of pontocerebellar hypoplasia and congenital microcephaly in which simplified gyral pattern was not observed in all of the patients. Here, we describe a series of nine patients from eight unrelated Egyptian families in whom whole exome sequencing detected a previously reported homozygous missense variant (c.295G>A, p.Ala99Thr) in PPIL1. Haplotype analysis confirmed that this variant has a founder effect in our population. All our patients displayed early onset drug-resistant epilepsy, profound developmental delay, and visual impairment. Remarkably, they presented with recognizable imaging findings showing profound microcephaly, hypoplastic frontal lobe and posteriorly predominant pachygyria, agenesis of corpus callosum with colpocephaly, and pontocerebellar hypoplasia. In addition, Dandy-Walker malformation was evident in three patients. Interestingly, four of our patients exhibited hematopoietic disorder (44% of cases). We compared the phenotype of our patients with other previously reported PPIL1 patients. Our results reinforce the hypothesis that the alterative splicing of PPIL1 causes a heterogeneous phenotype. Further, we affirm that hematopoietic disorder is a common feature of the condition and underscore the role of major spliceosomes in brain development.

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.

Biallelic FRA10AC1 variants cause a neurodevelopmental disorder with growth retardation.

The major spliceosome mediates pre-mRNA splicing by recognizing the highly conserved sequences at the 5' and 3' splice sites and the branch point. More than 150 proteins participate in the splicing process and are organized in the spliceosomal A, B, and C complexes. FRA10AC1 is a peripheral protein of the spliceosomal C complex and its ortholog in the green alga facilitates recognition or interaction with splice sites. We identified biallelic pathogenic variants in FRA10AC1 in five individuals from three consanguineous families. The two unrelated Patients 1 and 2 with loss-of-function variants showed developmental delay, intellectual disability, and no speech, while three siblings with the c.494_496delAAG (p.Glu165del) variant had borderline to mild intellectual disability. All patients had microcephaly, hypoplasia or agenesis of the corpus callosum, growth retardation, and craniofacial dysmorphism. FRA10AC1 transcripts and proteins were drastically reduced or absent in fibroblasts of Patients 1 and 2. In a heterologous expression system, the p.Glu165del variant impacts intrinsic stability of FRA10AC1 but does not affect its nuclear localization. By co-immunoprecipitation, we found ectopically expressed HA-FRA10AC1 in complex with endogenous DGCR14, another component of the spliceosomal C complex, while the splice factors CHERP, NKAP, RED, and SF3B2 could not be co-immunoprecipitated. Using an in vitro splicing reporter assay, we did not obtain evidence for FRA10AC1 deficiency to suppress missplicing events caused by mutations in the highly conserved dinucleotides of 5' and 3' splice sites in an in vitro splicing assay in patient-derived fibroblasts. Our data highlight the importance of specific peripheral spliceosomal C complex proteins for neurodevelopment. It remains possible that FRA10AC1 may have other and/or additional cellular functions, such as coupling of transcription and splicing reactions.

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.

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.

El-Hattab-Alkuraya syndrome caused by biallelic WDR45B pathogenic variants: Further delineation of the phenotype and genotype.

Homozygous pathogenic variants in WDR45B were first identified in six subjects from three unrelated families with global development delay, refractory seizures, spastic quadriplegia, and brain malformations. Since the initial report in 2018, no further cases have been described. In this report, we present 12 additional individuals from seven unrelated families and their clinical, radiological, and molecular findings. Six different variants in WDR45B were identified, five of which are novel. Microcephaly and global developmental delay were observed in all subjects, and seizures and spastic quadriplegia in most. Common findings on brain imaging include cerebral atrophy, ex vacuo ventricular dilatation, brainstem volume loss, and symmetric under-opercularization. El-Hattab-Alkuraya syndrome is associated with a consistent phenotype characterized by early onset cerebral atrophy resulting in microcephaly, developmental delay, spastic quadriplegia, and seizures. The phenotype appears to be more severe among individuals with loss-of-function variants whereas those with missense variants were less severely affected suggesting a potential genotype-phenotype correlation in this disorder. A brain imaging pattern emerges which is consistent among individuals with loss-of-function variants and could potentially alert the neuroradiologists or clinician to consider WDR45B-related El-Hattab-Alkuraya syndrome.

DTYMK is essential for genome integrity and neuronal survival.

Nucleotide metabolism is a complex pathway regulating crucial cellular processes such as nucleic acid synthesis, DNA repair and proliferation. This study shows that impairment of the biosynthesis of one of the building blocks of DNA, dTTP, causes a severe, early-onset neurodegenerative disease. Here, we describe two unrelated children with bi-allelic variants in DTYMK, encoding dTMPK, which catalyzes the penultimate step in dTTP biosynthesis. The affected children show severe microcephaly and growth retardation with minimal neurodevelopment. Brain imaging revealed severe cerebral atrophy and disappearance of the basal ganglia. In cells of affected individuals, dTMPK enzyme activity was minimal, along with impaired DNA replication. In addition, we generated dtymk mutant zebrafish that replicate this phenotype of microcephaly, neuronal cell death and early lethality. An increase of ribonucleotide incorporation in the genome as well as impaired responses to DNA damage were observed in dtymk mutant zebrafish, providing novel pathophysiological insights. It is highly remarkable that this deficiency is viable as an essential component for DNA cannot be generated, since the metabolic pathway for dTTP synthesis is completely blocked. In summary, by combining genetic and biochemical approaches in multiple models we identified loss-of-function of DTYMK as the cause of a severe postnatal neurodegenerative disease and highlight the essential nature of dTTP synthesis in the maintenance of genome stability and neuronal survival.

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.

Quantitative dissection of multilocus pathogenic variation in an Egyptian infant with severe neurodevelopmental disorder resulting from multiple molecular diagnoses.

Genomic sequencing and clinical genomics have demonstrated that substantial subsets of atypical and/or severe disease presentations result from multilocus pathogenic variation (MPV) causing blended phenotypes. In an infant with a severe neurodevelopmental disorder, four distinct molecular diagnoses were found by exome sequencing (ES). The blended phenotype that includes brain malformation, dysmorphism, and hypotonia was dissected using the Human Phenotype Ontology (HPO). ES revealed variants in CAPN3 (c.259C > G:p.L87V), MUSK (c.1781C > T:p.A594V), NAV2 (c.1996G > A:p.G666R), and ZC4H2 (c.595A > C:p.N199H). CAPN3, MUSK, and ZC4H2 are established disease genes linked to limb-girdle muscular dystrophy (OMIM# 253600), congenital myasthenia (OMIM# 616325), and Wieacker-Wolff syndrome (WWS; OMIM# 314580), respectively. NAV2 is a retinoic-acid responsive novel disease gene candidate with biological roles in neurite outgrowth and cerebellar dysgenesis in mouse models. Using semantic similarity, we show that no gene identified by ES individually explains the proband phenotype, but rather the totality of the clinically observed disease is explained by the combination of disease-contributing effects of the identified genes. These data reveal that multilocus pathogenic variation can result in a blended phenotype with each gene affecting a different part of the nervous system and nervous system-muscle connection. We provide evidence from this n = 1 study that in patients with MPV and complex blended phenotypes resulting from multiple molecular diagnoses, quantitative HPO analysis can allow for dissection of phenotypic contribution of both established disease genes and novel disease gene candidates not yet proven to cause human disease.

Fetal brain arrest broadens the spectrum of WDR81-related developmental brain malformations.

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.

Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition.

PURPOSE: Dioxygenases are oxidoreductase enzymes with roles in metabolic pathways necessary for aerobic life. 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL), encoded by HPDL, is an orphan paralogue of 4-hydroxyphenylpyruvate dioxygenase (HPD), an iron-dependent dioxygenase involved in tyrosine catabolism. The function and association of HPDL with human diseases remain unknown. METHODS: We applied exome sequencing in a cohort of over 10,000 individuals with neurodevelopmental diseases. Effects of HPDL loss were investigated in vitro and in vivo, and through mass spectrometry analysis. Evolutionary analysis was performed to investigate the potential functional separation of HPDL from HPD. RESULTS: We identified biallelic variants in HPDL in eight families displaying recessive inheritance. Knockout mice closely phenocopied humans and showed evidence of apoptosis in multiple cellular lineages within the cerebral cortex. HPDL is a single-exonic gene that likely arose from a retrotransposition event at the base of the tetrapod lineage, and unlike HPD, HPDL is mitochondria-localized. Metabolic profiling of HPDL mutant cells and mice showed no evidence of altered tyrosine metabolites, but rather notable accumulations in other metabolic pathways. CONCLUSION: The mitochondrial localization, along with its disrupted metabolic profile, suggests HPDL loss in humans links to a unique neurometabolic mitochondrial infantile neurodegenerative condition.

Expanding the KIF4A-associated phenotype.

Kinesin super family (KIF) genes encode motor kinesins, a family of evolutionary conserved proteins, involved in intracellular trafficking of various cargoes. These proteins are critical for various physiological processes including neuron function and survival, ciliary function and ciliogenesis, and cell-cycle progression. Recent evidence suggests that alterations in motor kinesin genes can lead to a variety of human diseases, including monogenic disorders. Neuropathies, impaired higher brain functions, structural brain abnormalities and multiple congenital anomalies (i.e., renal, urogenital, and limb anomalies) can result from pathogenic variants in many KIF genes. We expand the phenotype associated with KIF4A variants from developmental delay and intellectual disability with or without epilepsy to a congenital anomaly phenotype with hydrocephalus and various brain anomalies at the more severe end of phenotypic manifestations. Additional anomalies of the kidneys and urinary tract, congenital lymphedema, eye, and dental anomalies seem to be variably associated and overlap with clinical signs observed in other kinesinopathies. Caution still applies to missense variants, but hopefully, future work will further establish genotype-phenotype correlations in a larger number of patients and functional studies may give further insights into the complex function of KIF4A.

Asparagine Synthetase Deficiency with Intracranial Hemorrhage Can Mimic Molybdenum Cofactor Deficiency.

Here we report a consanguineous Egyptian family with two siblings presented with congenital microcephaly, early-onset epileptic encephalopathy, feeding difficulties, and early lethality. The condition was initially diagnosed as molybdenum cofactor deficiency as the brain imaging for one of them showed brain edema and intracranial hemorrhage in addition to the hypoplastic corpus callosum, vermis hypoplasia, and small-sized pons. Subsequently, whole exome sequencing identified a novel homozygous missense variant in exon 4 of ASNS gene c.397_398GT > CA (p.Val133Gln) confirming the diagnosis of asparagine synthetase deficiency syndrome. No discernible alternative cause for the intracranial hemorrhage was found. Our patient is the second to show asparagine synthetase deficiency and intracranial hemorrhage, thus confirming the involvement of ASNS gene. As such, it is important to consider asparagine synthetase deficiency syndrome in patients with microcephaly, brain edema, and neonatal intracranial hemorrhage.

A founder mutation in PEX12 among Egyptian patients in peroxisomal biogenesis disorder.

At least 14 distinctive PEX genes function in the biogenesis of peroxisomes. Biallelic alterations in the peroxisomal biogenesis factor 12 (PEX12) gene lead to Zellweger syndrome spectrum (ZSS) with variable clinical expressivity ranging from early lethality to mildly affected with long-term survival. Herein, we define 20 patients derived from 14 unrelated Egyptian families, 19 of which show a homozygous PEX12 in-frame (c.1047_1049del p.(Gln349del)) deletion. This founder mutation, reported rarely outside of Egypt, was associated with a uniformly severe phenotype. Patients showed developmental delay in early life followed by motor and mental regression, progressive hypotonia, unsteadiness, and lack of speech. Seventeen patients had sparse hair or partial alopecia, a striking feature that was not noted previously in PEX12. Neonatal cholestasis was manifested in 2 siblings. Neurodiagnostics showed consistent cerebellar atrophy and variable white matter demyelination, axonal neuropathy in about half, and cardiomyopathy in 10% of patients. A single patient with a compound heterozygous PEX12 mutation exhibited milder features with late childhood onset with gait disturbance and learning disability. Thus, the PEX12 relatively common founder mutation accounts for the majority of PEX12-related disease in Egypt and delineates a uniform clinical and radiographic phenotype.