Journal of pediatric genetics最新文献

The 4q deletion syndrome is an uncommon condition manifesting with broad clinical expression and phenotypic variability. We report a 5-year-old boy affected by 4q deletion syndrome who showed minor craniofacial features, growth failure, mild developmental delay, severe speech delay, and marked irascibility and aggressivity. Moreover, he showed precocious and crowded primary dentition, digital hyperlaxity, and congenital bilateral adducted thumbs, signs which were previously unreported in the syndrome. The array comparative genomic hybridization analysis revealed a 4q partial terminal deletion of ∼329.6 kb extending from 164.703.186 to 165.032.803 nt, which includes part of MARCH1 (membrane associated ring-CH-type finger 1) gene (OMIM#613331). Same rearrangement was found in his healthy mother. Clinical phenotype of the child and its relationship to the deleted region is presented with a revision of the cases having the same copy number losses from the literature and genomic variant databases.

Congenital heart disease (CHD), the most common major congenital anomaly, is associated with a genetic syndrome (chromosomal anomalies, genomic disorders, or monogenic disease) in 30% of patients. The aim of this systematic review was to evaluate if, in the neonatal setting, clinical clues that orient the diagnostic path can be identified. For this purpose, we revised the most frequent dysmorphic features described in newborns with CHD, comparing those associated with monogenic syndromes (MSG) with the ones reported in newborns with genomic disorders. For this systematic review according to PRISMA statement, we used PubMed, Medline, Google Scholar, Scopus database, and search terms related to CHD and syndrome. We found a wide range of dysmorphisms (ocular region, ears, mouth, and/or palate and phalangeal anomalies) detected in more than half of MSGs were found to be associated with CHDs, but those anomalies are also described in genomic rearrangements syndromes with equal prevalence. These findings confirmed that etiological diagnosis in newborns is challenging, and only the prompt and expert recognition of features suggestive of genetic conditions can improve the selection of appropriate, cost-effective diagnostic tests. However, in general practice, it is crucial to recognize clues that can suggest the presence of a genetic syndrome, and neonatologists often have the unique opportunity to be the first to identify abnormalities in the neonate.

A Silver syndrome is a rare autosomal dominant spastic paraparesis in which spasticity of the lower limbs is accompanied by amyotrophy of the small hand muscles. The causative gene is the Berardinelli-Seip congenital lipodystrophy 2 ( BSCL2) , which is related to a spectrum of neurological phenotypes. In the current study, we presented a 14-year-old male with a slowly progressive spastic paraparesis with urinary incontinence that later on exhibited atrophy and weakness in the thenar and dorsal interosseous muscles. Magnetic resonance imaging (MRI) revealed discrete atrophy of the corpus callosum isthmus and an extended next-generation sequencing panel identified a de novo heterozygous mutation in BSCL2 gene, c.269C > T p.(S90L). Various clinical expression and incomplete penetrance of BSCL2 gene mutations complicate the establishment of a genetic etiology for these cases. Therefore, Silver syndrome should be included in the differential diagnosis if the initial presentation is a spastic paraparesis by urinary involvement with childhood-onset, even with MRI atypical findings. This report described the first Iberian Silver syndrome case carrying a de novo c.269C > T p. (S90L) BSCL2 gene mutation.

Mutations in the DHDDS gene (MIM: 617836), encoding a subunit of dehydrodolichyl diphosphate synthase complex, have been recently implicated in very rare neurodevelopmental diseases. In total, five individuals carrying two de novo mutations in DHDDS have been reported so far, but genotype-phenotype correlations remain elusive. We reported a boy with a de novo mutation in DHDDS (NM_205861.3: c.G632A; p.Arg211Gln) featuring a complex neurological phenotype, including mild intellectual disability, impaired speech, complex hyperkinetic movements, and refractory epilepsy. We defined the electroclinical and movement disorder phenotype associated with the monoallelic form of the DHDDS -related neurodevelopmental disease and possible underlying dominant-negative mechanisms.

Glutaric acidemia type 1 (GA-1, OMIM 231670) is an autosomal recessive inborn error of metabolism caused by the deficiency of glutaryl-coenzyme A (CoA) dehydrogenase with most children presenting in infancy with encephalopathy, dystonia, and macrocephaly. In this article, we presented the clinical characteristics, molecular profile, and outcomes in 29 unrelated families with affected children (30 cases total). The mean age at onset of illness was 10 months (±14.58), whereas the mean age at referral for molecular diagnosis was 29.44 months (±28.11). Patients were residents of nine different states of India. Clinical presentation varied from acute encephalitis followed by neuroregression and chronic/insidious developmental delay. Neurological sequelae varied from asymptomatic (no sequelae, 2 patients) to moderate (5 patients) and severe (23 patients) sequelae. All patients underwent blood tandem mass spectrometry (TMS on dried blood spots) and/or urine gas chromatography mass spectrometry (GCMS). Neuroimaging demonstrated batwing appearance in 95% cases. Sanger's sequencing of GCDH , covering all exons and exon-intron boundaries, was performed for all patients. Variants identified include 15 novel coding variants: p.Met100Thr, p.Gly107Ser, p.Leu179Val, p.Pro217Ser, p. Phe236Leufs*107, p.Ser255Pro, p.Met266Leufs*2, p.Gln330Ter, p.Thr344Ile, p.Leu345Pro, p.Lys377Arg, p.Leu424Pro, p.Asn373Lys, p.Lys377Arg, p.Asn392Metfs*9, and nine known genetic variants such as p.Arg128Gln, p.Leu179Arg, p.Trp225Ter, p.Met339Val, p.Gly354Ser, p.Arg402Gln, p.Arg402Trp, p.His403Tyr, and p.Ala433Val (Ensembl transcript ID: ENST00000222214). Using in silico analysis, genetic variants were shown to be affecting the residues responsible for homotetramer formation of the glutaryl-CoA dehydrogenase protein. Treatment included oral carnitine, riboflavin, protein-restricted diet, lysine-deficient special formulae, and management of acute crises with intravenous glucose and hydration. However, the mortality (9/30, 27.58%) and morbidity was high in our cohort with only two patients affording the diet. Our study is the largest multicentric, genetic variant-proven series of glutaric aciduria type 1 from India till date.

17p13.3 microduplication syndrome has been associated with a clinical spectrum of phenotypes, and depending on the genes involved in the microduplication, it is categorized into two classes (Class I and Class II). We herein, describe two patients diagnosed with Class I 17p13.3 microduplication by BACs-on-Beads (BoBs) assay and further confirmed by fluorescence in situ hybridization (FISH). Our patients (Patient 1: 4-year-old male; Patient 2: 2-year-old male) presented with developmental delay, intellectual disability, and dysmorphic facial features. When compared with the literature, our patients manifested distinctive features (Patient 1: primary hypothyroidism; Patient 2: bilateral cryptorchidism) that were not previously described in the duplication 17p13.3 spectrum.

Background  Childhood ataxia with central nervous system hypomyelination (CACH) is a recently described childhood inherited white matter disease, caused by mutations in any of the five genes encoding eukaryotic translation initiation factor ( eIF2B ). Methods  Retrospective review of the charts of children with CACH was performed from January 2014 to March 2020 at tertiary care center from Southern India. Diagnosis was based on magnetic resonance imaging (MRI) criteria or genetic testing. Results  Total number of children with CACH enrolled were 18. Male/female ratio was 10:8. Mean age of presentation was 37.11 months (range =  6-144 months). Affected siblings were seen in five (28%) cases. All children had spasticity, ataxia, and diffuse white matter changes with similar signal as cerebrospinal fluid on all pulse sequences on MRI brain. Of the 18 children, only nine are alive. Duration of illness among deceased children was 9.6667 months (range = 2-16 months). Waxing and waning of symptoms were seen in seven cases. Genetic analysis of EIF2B gene was performed in five cases, among which three mutations were novel. Conclusion  A diagnosis of childhood ataxia with central nervous system hypomyelination should be considered in patients presenting with acute onset neuroregression following infection or trauma with associated neuroimaging showing classical white matter findings.

Introduction  Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare disorder caused by perturbation in renal reabsorption of magnesium and calcium. Biallelic pathogenic variants either in gene CLDN16 or CLDN19 are responsible for molecular defects. Most patients with CLDN19 variants have been associated with ocular involvements (FHHNCOI). Patient and Methods  We had a pediatric patient with hypercalciuric hypomagnesemia and bilateral chorioretinal atrophy. Metabolic profiling and radiology examinations were performed, in addition to whole exome sequencing (WES) used for detection of the causative variant. Results  Analysis of WES revealed a homozygous c.223G > A (p.G75S) variant in CLDN19 . MutationTaster and Combined Annotation-Dependent Depletion support its deleterious effect and SHERLOC's criteria put it in pathogenic category. This variant is previously reported in compound heterozygous state with other known pathogenic variant. As far as we know, it is the first report of this variant in homozygous state. Conclusion  The variant found in our patient is pathogenic and compatible with FHHNCOI characteristics. WES is an advantageous tool in molecular diagnosis and finding genetic pathology of this disease. In line with other reports, ocular abnormalities are variable in patients with CLDN19 mutations, and chronic kidney disease and retinal damages must be considered in this group.

We reported on a 3-year-old girl child patient with the presence of trigonocephaly, broad nasal bridge, flattened occiput, and midface hypoplasia. Formal assessment of her development profile demonstrated expressive and receptive language delays, fine and gross motor delays, and no imaginative or symbolic representative play. Investigation of the etiology of her developmental delays revealed a genetic diagnosis of a 9p24 deletion by chromosomal microarray analysis. The possibility of an additional co-occurring disorder of autism spectrum disorder (ASD) was also raised by a referring clinician. This case report highlighted the clinical dilemma of diagnosing ASD in those with existing genetic syndromes.