AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder.

Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acid synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH) due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a potentially treatable early-onset neurodegenerative disease.

Biallelic variants in HECT E3 paralogs, HECTD4 and UBE3C, encoding ubiquitin ligases cause neurodevelopmental disorders that overlap with Angelman syndrome.

PURPOSE: Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified. METHODS: Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. RESULTS: In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect. CONCLUSION: HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome.

Cone-beam computed tomographic analysis of maxillary sinus septa among Yemeni population: a cross-sectional study.

BACKGROUND: Maxillary sinus septa increase perforation risk of Schneiderian membrane during the sinus floor elevation (SFE). Cone Beam Computed Tomography (CBCT) allows for a more precise assessment of the septal position; thus, preoperative CBCT analysis is substantial to avoid possible complications. This study aims to investigate the 3D characteristics of the maxillary sinus septa based on CBCT images. To our knowledge, no study reported the CBCT-based investigation for the sinus septa among Yemeni population. MATERIALS AND METHODS: This is a retrospective cross-sectional analysis of 880 sinus CBCT images 440 patients. The septa prevalence, locations, orientations, morphology, and associated factors were analyzed. The effect of age, gender, and dental status on the sinus septa and the relationship between sinus membrane pathology and sinus septa were also analyzed. Anatomage (Invivo version 6) was used for CBCT images analysis. Descriptive and analytical statistics were performed, and a P-value < 0.05 was significantly considered. RESULTS: The maxillary sinus septa were found among 63.9% of patients and 47% of sinuses. The average septa height was 5.2 mm. 15.7% of patients had septa in the right maxilla, 18% in the left, and 30.2% in both. Gender, age, and dental condition had no influence on the presence of septa, and septa presence did not influence sinus membrane pathology. Many septa originated from the floor (54.5%), located in the middle (43%), with coronal orientation (66%) and complete configuration (58.2%). CONCLUSION: Based on our findings, the septa prevalence, locations, orientations, and morphology were significant and equivalent to the highest recorded in the literature yet. Thus, when sinus floor elevation is planned, CBCT imaging of the maxillary sinus is recommended for safe dental implantation.

Further delineation of GEMIN4 related neurodevelopmental disorder with microcephaly, cataract, and renal abnormalities syndrome.

Pathogenic variants in GEMIN4 have recently been linked to an inherited autosomal recessive neurodevelopmental disorder characterized with microcephaly, cataracts, and renal abnormalities (NEDMCR syndrome). This report provides a retrospective review of 16 patients from 11 unrelated Saudi consanguineous families with GEMIN4 mutations. The cohort comprises 11 new and unpublished clinical details from five previously described patients. Only two missense, homozygous, pathogenic variants were found in all affected patients, suggesting a founder effect. All patients shared global developmental delay with variable ophthalmological, renal, and skeletal manifestations. In addition, we knocked down endogenous Drosophila GEMIN4 in neurons to further investigate the mechanism of the functional defects in affected patients. Our fly model findings demonstrated developmental defects and motor dysfunction suggesting that loss of GEMIN4 function is detrimental in vivo; likely similar to human patients. To date, this study presents the largest cohort of patients affected with GEMIN4 mutations. Considering that identifying GEMIN4 defects in patients presenting with neurodevelopmental delay and congenital cataract will help in early diagnosis, appropriate management and prevention plans that can be made for affected families.

Clinical characterization and further confirmation of the autosomal recessive SLC12A2 disease.

Heterozygous pathogenic variants in SLC12A2 are reported in patients with nonsyndromic hearing loss. Recently, homozygous loss-of-function variants have been reported in two patients with syndromic intellectual disability, with or without hearing loss. However, the clinical and molecular spectrum of SLC12A2 disease has yet to be characterized and confirmed. Using whole-exome sequencing, we detected a homozygous splicing variant in four patients from two independent families with severe developmental delay, microcephaly, respiratory abnormalities, and subtle dysmorphic features, with or without congenital hearing loss. We also reviewed the reported cases with pathogenic variants associated with autosomal dominant and recessive forms of the SLC12A2 disease. About 50% of the cases have syndromic and nonsyndromic congenital hearing loss. All patients harboring the recessive forms of the disease presented with severe global developmental delay. Interestingly, all reported variants are located in the c-terminal domain, suggesting a critical role of this domain for the proper function of the encoded co-transporter protein. In conclusion, our study provides an additional confirmation of the autosomal recessive SLC12A2 disease.

Clinical, molecular, and biochemical delineation of asparagine synthetase deficiency in Saudi cohort.

PURPOSE: Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD. METHODS: We retrospectively collected the clinical and molecular information on 13 families with ASNSD from the major metabolic clinics in Saudi Arabia. RESULTS: The major phenotypes included congenital microcephaly (100%), facial dysmorphism (100%), global developmental delay (100%), brain abnormalities (100%), spasticity (86%), and infantile-onset seizures (93%). Additional unreported phenotypes included umbilical hernia, osteopenia, eczema, lung hypoplasia, and hearing loss. Overall, seven homozygous variants accounted for ASNSD. The p.Tyr398Cys and p.Asn75Ile variants accounted for 54% of the cases. The clinical sensitivity and specificity of the proposed biochemical analysis of cerebrospinal fluid (CSF) for the detection of patients with ASNSD were 83% and 98%, respectively. CONCLUSION: Our study describes the largest reported ASNSD cohort with clinical, molecular, and biochemical characterization. Taking into consideration the suboptimal sensitivity of biochemical screening, the delineation of the phenotype variant spectrum is of diagnostic utility for accurate diagnosis, prognosis, counseling, and carrier screening.

MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects.

Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile-onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17-related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with nine novel MPV17 pathogenic variants. We summarize the clinical features of all 100 affected individuals and review the total 48 MPV17 pathogenic variants. The vast majority of affected individuals presented with an early-onset encephalohepatopathic disease characterized by hepatic and neurological manifestations, failure to thrive, lactic acidemia, and mtDNA depletion detected mainly in liver tissue. Rarely, MPV17 deficiency can cause a late-onset neuromyopathic disease characterized by myopathy and peripheral neuropathy with no or minimal liver involvement. Approximately half of the MPV17 pathogenic variants are missense. A genotype with biallelic missense variants, in particular homozygous p.R50Q, p.P98L, and p.R41Q, can carry a relatively better prognosis.

Mutations in the NHEJ component XRCC4 cause primordial dwarfism.

Non-homologous end joining (NHEJ) is a key cellular process ensuring genome integrity. Mutations in several components of the NHEJ pathway have been identified, often associated with severe combined immunodeficiency (SCID), consistent with the requirement for NHEJ during V(D)J recombination to ensure diversity of the adaptive immune system. In contrast, we have recently found that biallelic mutations in LIG4 are a common cause of microcephalic primordial dwarfism (MPD), a phenotype characterized by prenatal-onset extreme global growth failure. Here we provide definitive molecular genetic evidence supported by biochemical, cellular, and immunological data for mutations in XRCC4, encoding the obligate binding partner of LIG4, causing MPD. We report the identification of biallelic mutations in XRCC4 in five families. Biochemical and cellular studies demonstrate that these alterations substantially decrease XRCC4 protein levels leading to reduced cellular ligase IV activity. Consequently, NHEJ-dependent repair of ionizing-radiation-induced DNA double-strand breaks is compromised in XRCC4 cells. Similarly, immunoglobulin junctional diversification is impaired in cells. However, immunoglobulin levels are normal, and individuals lack overt signs of immunodeficiency. Additionally, in contrast to individuals with LIG4 mutations, pancytopenia leading to bone marrow failure has not been observed. Hence, alterations that alter different NHEJ proteins give rise to a phenotypic spectrum, from SCID to extreme growth failure, with deficiencies in certain key components of this repair pathway predominantly exhibiting growth deficits, reflecting differential developmental requirements for NHEJ proteins to support growth and immune maturation.

FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance.

An increasing number of mitochondrial diseases are found to be caused by pathogenic variants in nuclear encoded mitochondrial aminoacyl-tRNA synthetases. FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) which transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, a total of 21 subjects with FARS2 deficiency have been reported to date with a spectrum of disease severity that falls between two phenotypes; early onset epileptic encephalopathy and a less severe phenotype characterized by spastic paraplegia. In this report, we present an additional 15 individuals from 12 families who are mostly Arabs homozygous for the pathogenic variant Y144C, which is associated with the more severe early onset phenotype. The total number of unique pathogenic FARS2 variants known to date is 21 including three different partial gene deletions reported in four individuals. Except for the large deletions, all variants but two (one in-frame deletion of one amino acid and one splice-site variant) are missense. All large deletions and the single splice-site variant are in trans with a missense variant. This suggests that complete loss of function may be incompatible with life. In this report, we also review structural, functional, and evolutionary significance of select FARS2 pathogenic variants reported here.

Cutaneous vasculitis in systemic lupus erythematosus patients: potential key players and implications.

OBJECTIVES: The aim of the present work was to study the clinical characteristics of cutaneous vasculitis (CV) in systemic lupus erythematosus (SLE) patients and find possible potential key players in its development and implicated associations with the disease manifestations. PATIENTS AND METHODS: Fifty adult female SLE patients underwent full history taking, thorough clinical examination and laboratory investigations. The SLE Disease Activity Index (SLEDAI) and accumulated damage using the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC/ACR DI) were assessed. RESULTS: The mean age of the patients was 29.1 ± 6.1 years and was significantly lower in those with CV (p = 0.018). The disease duration was 4.9 ± 3.7 years. CV was present in 30% of the patients. Musculoskeletal manifestations and hypocomplementemia were present in all patients with CV. The SLEDAI and SLICC/ACR DI tended to be higher in those with CV. Complement (C3 and C4) was significantly consumed in CV patients (p < 0.0001). Antiphospholipids were comparable between those with and without CV. Lupus nephritis, cardiovascular manifestations and Sjögren syndrome were significantly linked to the development of CV (p = 0.025, p = 0.023 and p < 0.0001, respectively). Both C3 and C4 showed a high sensitivity (93.3% and 86.7%) to detect CV in SLE at cut-off values below 81.4 mg/dl and 16.8 mg/dl, respectively. CONCLUSION: CV is closely related to hypocomplementemia but not to antiphospholipids and is associated with lupus nephritis, musculoskeletal manifestations and Sjögren syndrome.

Anti-dsDNA titre in female systemic lupus erythematosus patients: relation to disease manifestations, damage and antiphospholipid antibodies.

Background Attempts are ongoing to unveil unresolved queries about anti-double-stranded deoxyribonucleic acid (anti-dsDNA), their precise pathogenic effects and to what extent blocking them would be a useful therapeutic goal. Objectives The aim of the present study was to determine the anti-dsDNA antibodies titre in systemic lupus erythematosus (SLE) patients and investigate their relation to the disease characteristics, activity, damage and antiphospholipid autoantibodies (aPL). Methods Seventy female SLE patients and 35 age- and sex-matched controls were included. The anti-dsDNA level and aPL were measured. Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI) were assessed. Results The mean age of the patients was 27.5 ± 5.1 years, disease duration 7.7 ± 5.4 years, and SLEDAI and SLICC/ACR-DI scores were 6.8 ± 8.04 and 1.2 ± 1.3, respectively. Anti-dsDNA was positive in 61.4% of the patients and the titre (133.2 ± 100.5 IU/ml) was significantly higher compared to controls (22.03 ± 17.2 IU/ml) ( p < 0.0001). The anti-dsDNA level was significantly increased in those with musculoskeletal manifestations ( p = 0.007) and positive anti-ß2 glycoprotein (anti-ß2GP) ( p = 0.037) and decreased in those with neuropsychiatric manifestations ( p = 0.004) and those receiving cyclophosphamide (CYC) ( p = 0.013). The anti-dsDNA level tended to be higher in active patients. The anti-dsDNA titre significantly correlated with the erythrocyte sedimentation rate ( p = 0.001), anticardiolipin IgG and IgA antibodies ( p = 0.008) and anti-ß2GP IgG ( p = 0.03) and IgA ( p = 0.002) and inversely with the total leucocytic count ( p < 0.0001) and SLICC/ACR-DI ( p = 0.001). Conclusion Anti-dsDNA is remarkably increased in SLE patients especially those with musculoskeletal manifestations and aPL. A protective role seems likely in those with neuropsychiatric manifestations and those receiving CYC and may form a shield against disease tissue damage.

Impact of allergy on children with attention deficit hyperactivity disorder.

Summary: Background. Attention deficit hyperactivity disorder (ADHD) is commonly present worldwide, causing serious problems to those affected. ADHD was suggested to be secondary to allergic disorder or its medication. Both ADHD and allergy depend on complex environmental and genetic interaction, and they meet the hypersensitivity criteria. Objective. Detect the percentage of allergy in ADHD children, the common allergic disorders and allergens, and the effect of allergy on symptom and severity of ADHD. Material and methods. 100 children with ADHD were subjected to psychiatric assessment for ADHD type and severity, history of allergy, skin prick test to common environmental allergens, serum total IgE levels and open food challenge. Co-morbid neuropsychiatric disorders, below average intelligence quotient (IQ), and chronic illnesses were excluded. A control of 60 healthy children was chosen to compare the results of skin prick test and serum total IgE levels. Results. 35 ADHD children (35%) were allergic. Most cases had combined allergic rhinitis and bronchial asthma (25%). Common allergens were hay dust (43%) followed by different pollens (37.5%). There were statistical significant differences between coexistence of allergy, type of ADHD, early onset and severity of symptoms. Conclusion. Children with ADHD had an increased prevalence of allergic diseases. Evaluation of allergy in ADHD is mandatory, to decrease the burden of the condition.

Functional analysis of novel DEAF1 variants identified through clinical exome sequencing expands DEAF1-associated neurodevelopmental disorder (DAND) phenotype.

Deformed epidermal autoregulatory factor-1 (DEAF1), a transcription factor essential for central nervous system and early embryonic development, has recently been implicated in a series of intellectual disability-related neurodevelopmental anomalies termed, in this study, as DEAF1-associated neurodevelopmental disorder (DAND). We identified six potentially deleterious DEAF1 variants in a cohort of individuals with DAND via clinical exome sequencing (CES) and in silico analysis, including two novel de novo variants: missense variant c.634G > A p.Gly212Ser in the SAND domain and deletion variant c.913_915del p.Lys305del in the NLS domain, as well as c.676C > T p.Arg226Trp, c.700T > A p.Trp234Arg, c.737G > C p.Arg246Thr, and c.791A > C p.Gln264Pro. Luciferase reporter, immunofluorescence staining, and electrophoretic mobility shift assays revealed that these variants had decreased transcriptional repression activity at the DEAF1 promoter and reduced affinity to consensus DEAF1 DNA binding sequences. In addition, c.913_915del p.K305del localized primarily to the cytoplasm and interacted with wild-type DEAF1. Our results demonstrate that variants located within the SAND or NLS domains significantly reduce DEAF1 transcriptional regulatory activities and are thus, likely to contribute to the underlying clinical concerns in DAND patients. These findings illustrate the importance of experimental characterization of variants with uncertain significance identified by CES to assess their potential clinical significance and possible use in diagnosis.

Molecular and clinical spectra of FBXL4 deficiency.

F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4-related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype-phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies.

Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance.

Nuclear genetic disorders causing mitochondrial DNA (mtDNA) depletion are clinically and genetically heterogeneous, and the molecular etiology remains undiagnosed in the majority of cases. Through whole-exome sequencing, we identified recessive nonsense and splicing mutations in FBXL4 segregating in three unrelated consanguineous kindreds in which affected children present with a fatal encephalopathy, lactic acidosis, and severe mtDNA depletion in muscle. We show that FBXL4 is an F-box protein that colocalizes with mitochondria and that loss-of-function and splice mutations in this protein result in a severe respiratory chain deficiency, loss of mitochondrial membrane potential, and a disturbance of the dynamic mitochondrial network and nucleoid distribution in fibroblasts from affected individuals. Expression of the wild-type FBXL4 transcript in cell lines from two subjects fully rescued the levels of mtDNA copy number, leading to a correction of the mitochondrial biochemical deficit. Together our data demonstrate that mutations in FBXL4 are disease causing and establish FBXL4 as a mitochondrial protein with a possible role in maintaining mtDNA integrity and stability.

ADAT3-related intellectual disability: Further delineation of the phenotype.

ADAT3-related intellectual disability has been recently described in 24 individuals from eight Saudi families who had cognitive impairment and strabismus. Other common features included growth failure, microcephaly, tone abnormalities, epilepsy, and nonspecific brain abnormalities. A single homozygous founder mutation (c.382G>A:p.(V128M)) in the ADAT3 gene, which encodes a protein that functions in tRNA editing, was identified in all affected individuals. In this report, we present additional 15 individuals from 11 families (10 Saudis and 1 Emirati) who are homozygous for the same founder mutation. In addition to the universal findings of intellectual disability and strabismus, the majority exhibited microcephaly and growth failure. Additional features not reported in the original cohort include dysmorphic facial features (prominent forehead, up-slanted palpebral fissures, epicanthus, and depressed nasal bridge), behavioral problems (hyperactivity and aggressiveness), recurrent otitis media, and growth hormone deficiency. ADAT3-related intellectual disability is an important recognizable cause of intellectual disability in Arabia.

ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder.

BACKGROUND: There are numerous nuclear genes that cause mitochondrial disorders and clinically and genetically heterogeneous disorders whose aetiology often remains unsolved. In this study, we aim to investigate an autosomal recessive syndrome causing leukodystrophy and neuroregression. We studied six patients from five unrelated consanguineous families. METHODS: Patients underwent full neurological, radiological, genetic, metabolic and dysmorphological examinations. Exome sequencing coupled with autozygosity mapping, Sanger sequencing, microsatellite haplotyping, standard and molecular karyotyping and whole mitochondrial DNA sequencing were used to identify the genetic cause of the syndrome. Immunohistochemistry, transmission electron microscopy, confocal microscopy, dipstick assays, quantitative PCR, reverse transcription PCR and quantitative reverse transcription PCR were performed on different tissue samples from the patients. RESULTS: We identified a homoallelic missense founder mutation in ISCA2 leading to mitochondrial depletion and reduced complex I activity as well as decreased ISCA2, ISCA1 and IBA57 expression in fibroblasts. MRI indicated similar white matter abnormalities in the patients. Histological examination of the skeletal muscle showed mild to moderate variation in myofibre size and the presence of many randomly distributed atrophic fibres. CONCLUSIONS: Our data demonstrate that ISCA2 deficiency leads to a hereditary mitochondrial neurodegenerative white matter disease in infancy.

Novel STAMBP mutation and additional findings in an Arabic family.

Microcephaly-capillary malformation syndrome (MIC-CAP syndrome) is a newly recognized autosomal recessive congenital neurocutaneous central nervous system disorder characterized by severe microcephaly, early-onset seizures, profound psychomotor disability, and multiple cutaneous capillary lesions. In addition, affected patients have variable dysmorphic facial features and hypoplastic distal phalanges. It is distinctively caused by mutations in a newly characterized gene, STAMBP, encoding the deubiquitinating (DUB) isopeptidase that has a key role in cell surface receptor-mediated endocytosis and sorting. Herein, we describe an Arab family of two siblings with classic features of MIC-CAP syndrome that harbor a novel predicted splice mutation in STAMBP, which additionally display previously unreported findings of congenital hypothyroidism and alopecia areata.

Novel homozygous DEAF1 variant suspected in causing white matter disease, intellectual disability, and microcephaly.

DEAF1 encodes a transcriptional binding factor and is a regulator of serotonin receptor 1A. Its protein has a significant expression in the neurons of different brain regions and is involved in early embryonic development. In addition, its role in neural tube development is evident from the knockout mouse as many homozygotes have exencephaly. Heterozygous mutations of this gene have been linked to intellectual disability in addition to the gene's involvement in major depression, suicidal tendencies, and panic disorder. In this clinical report, we describe two children from a consanguineous family with intellectual disability, microcephaly, and hypotonia. The brain MRI of both patients showed bilateral and symmetrical white matter abnormalities, and one of the patients had a seizure disorder. Using whole exome sequencing combined with homozygosity mapping, a homozygous p.R226W (c.676C>T) mutation in DEAF1 was found in both patients. Furthermore, sequencing analysis confirmed complete segregation in tested family members and absence of the mutation in control cohort (n = 650). The mutation is located in a highly conserved structural domain that mediates DNA binding and therefore regulates transcriptional activity of its target molecules. This study indicates, for the first time to our knowledge, a hereditary role of DEAF1 in white matter abnormalities, microcephaly and syndromic intellectual disability.