Distal Arthrogryposis type 5D (DA5D) is characterized by congenital contractures involving the distal joints, short stature, scoliosis, ptosis, astigmatism, and dysmorphic features. It is inherited ...in an autosomal recessive manner, and it is a result of homozygous or compound heterozygous variants in the ECEL1 gene. Here, we report two patients of Sardinian origin harboring a new intronic homozygous variant in ECEL1 (c.1507-9G>A), which was predicted to affect mRNA splicing by activating a cryptic acceptor site. The frequency of the variant is very low in the general human population, and its presence in our families can be attributed to a founder effect. This study provides an updated review of the known causative mutations of the ECEL1 gene, enriching the allelic spectrum to include the noncoding sequence.
To identify whether parent-of-origin effects (POE) of the 15q11.2 BP1-BP2 microdeletion are associated with differences in clinical features in individuals inheriting the deletion, we collected 71 ...individuals reported with phenotypic data and known inheritance from a clinical cohort, a research cohort, the DECIPHER database, and the primary literature. Chi-squared and Mann-Whitney U tests were used to test for differences in specific and grouped clinical symptoms based on parental inheritance and proband gender. Analyses controlled for sibling sets and individuals with additional variants of uncertain significance (VOUS). Among all probands, maternal deletions were associated with macrocephaly (
= 0.016) and autism spectrum disorder (ASD;
= 0.02), while paternal deletions were associated with congenital heart disease (CHD;
= 0.004). Excluding sibling sets, maternal deletions were associated with epilepsy as well as macrocephaly (
< 0.05), while paternal deletions were associated with CHD and abnormal muscular phenotypes (
< 0.05). Excluding sibling sets and probands with an additional VOUS, maternal deletions were associated with epilepsy (
= 0.019) and paternal deletions associated with muscular phenotypes (
= 0.008). Significant gender-based differences were also observed. Our results supported POEs of this deletion and included macrocephaly, epilepsy and ASD in maternal deletions with CHD and abnormal muscular phenotypes seen in paternal deletions.
Hereditary spastic paraplegias (HSP) are clinical and genetic heterogeneous diseases with more than 80 disease genes identified thus far. Studies on large cohorts of HSP patients showed that, by ...means of current technologies, the percentage of genetically solved cases is close to 50%. Notably, the percentage of molecularly confirmed diagnoses decreases significantly in sporadic patients. To describe our diagnostic molecular genetic approach on patients with pediatric-onset pure and complex HSP, 47 subjects with HSP underwent molecular screening of 113 known and candidate disease genes by targeted capture and massively parallel sequencing. Negative cases were successively analyzed by multiplex ligation-dependent probe amplification (MLPA) analysis for the
SPAST
gene and high-resolution SNP array analysis for genome-wide CNV detection. Diagnosis was molecularly confirmed in 29 out of 47 (62%) patients, most of whom had clinical diagnosis of cHSP. Although
SPG11
and
SPG4
remain the most frequent cause of, respectively, complex and pure HSP, a large number of pathogenic variants were disclosed in
POLR3A
,
FA2H
,
DDHD2
,
ATP2B4
,
ENTPD1
,
ERLIN2
,
CAPN1
,
ALS2
,
ADAR1
,
RNASEH2B
,
TUBB4A
,
ATL1
, and
KIF1A
. In a subset of these disease genes, phenotypic expansion and novel genotype-phenotype correlations were recognized. Notably, SNP array analysis did not provide any significant contribution in increasing the diagnostic yield. Our findings document the high diagnostic yield of targeted sequencing for patients with pediatric-onset, complex, and pure HSP. MLPA for
SPAST
and SNP array should be limited to properly selected cases based on clinical suspicion.
Complex genomic rearrangements (CGRs) are structural variants arising from two or more chromosomal breaks, which are challenging to characterize by conventional or molecular cytogenetic analysis ...(karyotype and FISH). The integrated approach of standard and genomic techniques, including optical genome mapping (OGM) and genome sequencing, is crucial for disclosing and characterizing cryptic chromosomal rearrangements at high resolutions. We report on a patient with a complex developmental and epileptic encephalopathy in which karyotype analysis showed a de novo balanced translocation involving the long arms of chromosomes 2 and 18. Microarray analysis detected a 194 Kb microdeletion at 2q24.3 involving the SCN2A gene, which was considered the likely translocation breakpoint on chromosome 2. However, OGM redefined the translocation breakpoints by disclosing a paracentric inversion at 2q24.3 disrupting SCN1A. This combined genomic high-resolution approach allowed a fine characterization of the CGR, which involves two different chromosomes with four breakpoints. The patient’s phenotype resulted from the concomitant loss of function of SCN1A and SCN2A.
Interstitial deletions involving 6q chromosomal region are rare. Less than 30 patients have been described to date, and fewer have been characterized by high-resolution techniques, such as ...chromosomal microarray. Deletions involving 6q21q22.1 region are associated with an extremely wide and heterogeneous clinical spectrum, thus genotype-phenotype correlation based on the size of the rearranged region and on the involved genes is complex, even among individuals with overlapping deletions. Here we describe the phenotypic and molecular characterization of a new 6q interstitial deletion in a girl with developmental delay, intellectual disability, cerebellar vermis hypoplasia, facial peculiar characteristics, ataxia and ocular abnormalities. Microarray analysis of the proposita revealed a 7.9 Mb interstitial
deletion at 6q21q22.1 chromosomal region, which spanned from nucleotides 108,337,770 to 116,279,453 (GRCh38/hg38). The present case, alongside with a systematic review of the literature, provides further evidence that could aid to the definition of the Smallest Region of Overlap and of the genomic traits that are associated with particular phenotypes, focusing on neurological findings and especially on cerebellar anomalies.
X-linked
gene has recently been pointed as one of the most interesting candidates for involvement in neurodevelopmental disorders (NDs), such as intellectual disability (ID) and autism spectrum ...disorder (ASD).
encodes the patched domain-containing protein 1 (
), which is mainly expressed in the developing brain and adult brain tissues. To date, major studies have focused on the biological function of the
gene, while the mechanisms underlying neuronal alterations and the cognitive-behavioral phenotype associated with mutations still remain unclear.
With the aim of incorporating information on the clinical profile of affected individuals and enhancing the characterization of the genotype-phenotype correlation, in this study, we analyze the clinical features of four individuals (two children and two adults) in which array-CGH detected a
deletion or in which panel for screening non-syndromal XLID (X-linked ID) detected a
gene variant. We define the neuropsychological and psychopathological profiles, providing quantitative data from standardized evaluations. The assessment consisted of clinical observations, structured interviews, and parent/self-reported questionnaires.
Our descriptive analysis align with previous findings on the involvement of the
gene in NDs. Specifically, our patients exhibited a clinical phenotype characterized by psychomotor developmental delay- ID of varying severity. Interestingly, while ID during early childhood was associated with autistic-like symptomatology, this interrelation was no longer observed in the adult subjects. Furthermore, our cohort did not display peculiar dysmorphic features, congenital abnormalities or comorbidity with epilepsy.
Our analysis shows that the psychopathological and behavioral comorbidities along with cognitive impairment interfere with development, therefore contributing to the severity of disability associated with
gene mutation. Awareness of this profile by professionals and caregivers can promote prompt diagnosis as well as early cognitive and occupational enhancement interventions.
We report on a patient born to consanguineous parents, presenting with Growth Hormone Deficiency (GHD) and osteoporosis. SNP-array analysis and exome sequencing disclosed long contiguous stretches of ...homozygosity and two distinct homozygous variants in
(Q6H) and
(E1361K) genes. The
variant was described as causative in a few subjects with an incompletely penetrant dominant form of combined pituitary hormone deficiency (CPHD). The
variant is rare, and so far it has never been found in a homozygous form. Segregation analysis showed that both variants were inherited from heterozygous unaffected parents. Present results further elucidate the inheritance pattern of
variants and recommend assessing the clinical impact of variants located in C-terminal propeptide of
gene for their potential association with rare recessive and early onset forms of osteoporosis.
Silver–Russell syndrome is an imprinting disorder characterised by pre- and post-natal growth retardation and several heterogeneous molecular defects affecting different human genomic loci. In the ...majority of cases, the molecular defect is the loss of methylation (LOM) of the H19/IGF2 differentially methylated region (DMR, also known as IC1) at the telomeric domain of the 11p15.5 imprinted genes cluster, which causes the altered expression of the growth controlling genes, IGF2 and H19. Very rarely, the LOM also affects the KCNQ1OT1 DMR (also known as IC2) at the centromeric domain, resulting in an SRS phenotype by an unknown mechanism. In this study, we report on two cases with SRS features and a LOM of either IC1 and IC2. In one case, this rare and complex epimutation was secondary to a de novo mosaic in cis maternal duplication, involving the entire telomeric 11p15.5 domain and part of the centromeric domain but lacking CDKN1C. In the second case, neither the no 11p15.5 copy number variant nor the maternal-effect subcortical maternal complex (SCMC) variant were found to be associated with the epimutation, suggesting that it arose as a primary event. Our findings further add to the complexity of the molecular genetics of SRS and indicate how the LOM in both 11p15.5 DMRs may result from different molecular mechanisms.
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