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.
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.
Our results add the infantile onset as a new distinct phenotype of the disease showing progressive atrophy, bilateral degeneration of basal ganglia, and cystic encephalomalacia. Further, we suggest that the site of the variant rather than its type is strongly correlated with the disease onset. The clinical phenotypes of PNPLA8, despite being largely distinct from each other, exhibit a clear spectrum with clinical features always aligning with different age of onset.
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.
A homozygous founder variant in PPIL1 gene leads to a recognizable type of pontocerebellar hypoplasia associated with developmental brain malformation and congenital severe microcephaly.
Pseudouridylation is the most common post-transcriptional modification, wherein uridine is isomerized into 5-ribosyluracil (pseudouridine, Ψ). The resulting increase in base stacking and creation of ...additional hydrogen bonds are thought to enhance RNA stability. Pseudouridine synthases are encoded in humans by 13 genes, two of which are linked to Mendelian diseases:
PUS1
and
PUS3
. Very recently,
PUS7
mutations were reported to cause intellectual disability with growth retardation. We describe two families in which two different homozygous
PUS7
mutations (missense and frameshift deletion) segregate with a phenotype comprising intellectual disability and progressive microcephaly. Short stature and hearing loss were variable in these patients. Functional characterization of the two mutations confirmed that both result in decreased levels of Ψ
13
in tRNAs. Furthermore, the missense variant of the
S. cerevisiae
ortholog failed to complement the growth defect of
S. cerevisiae pus7Δ trm8Δ
mutants. Our results confirm that
PUS7
is a bona fide Mendelian disease gene and expand the list of human diseases caused by impaired pseudouridylation.
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.
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.
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.
Primary microcephaly is a clinical phenotype in which the head circumference is significantly reduced at birth due to abnormal brain development, primarily at the cortical level. Despite the marked ...genetic heterogeneity, most primary microcephaly-linked genes converge on mitosis regulation. Two consanguineous families segregating the phenotype of severe primary microcephaly, spasticity and failure to thrive had overlapping autozygomes in which exome sequencing identified homozygous splicing variants in
CIT
that segregate with the phenotype within each family.
CIT
encodes citron, an effector of the Rho signaling that is required for cytokinesis specifically in proliferating neuroprogenitors, as well as for postnatal brain development. In agreement with the critical role assigned to the kinase domain in effecting these biological roles, we show that both splicing variants predict variable disruption of this domain. The striking phenotypic overlap between
CIT
-mutated individuals and the knockout mice and rats that are specifically deficient in the kinase domain supports the proposed causal link between
CIT
mutation and primary microcephaly in humans.
Lenz–Majewski syndrome in a patient from Egypt Afifi, Hanan H.; Abdel‐Hamid, Mohamed S.; Mehrez, Mennat I. ...
American journal of medical genetics. Part A,
October 2019, 2019-10-00, 20191001, Letnik:
179, Številka:
10
Journal Article
Recenzirano
Lenz–Majewski syndrome (LMS) is an extremely rare type of cutis laxa caused by dominant mutations in PTDSS1 gene. We report an Egyptian patient who presented with cutis laxa, brachydactyly, and ...progeroid features. LMS syndrome was suspected and a previously reported de novo heterozygous missense mutation (c.284G > T, p.R95L) in PTDSS1 was identified. To the best of our knowledge, nine molecularly proven patients with LMS from different ethnicities have been reported. Our patient is the first report from the Middle East and the tenth molecularly proven patient reported to date. His clinical features were in accordance with LMS syndrome. In addition, his hands X‐ray images showed hypoplastic or absent middle and proximal phalanges but sparing the thumbs. This hand patterning was similarly observed before. Further, he had relatively large and convex fingernails. Our report highlights this unique hand patterning and suggests these signs should be considered among the diagnostic criteria of LMS. Further reports of patients with PTDSS1 mutations are necessary to further elucidate the detailed clinical features of LMS syndrome.
PDF
