To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The ...smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which
,
,
,
and
are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only
,
and
genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that
is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of
and better define how the two contiguous genes,
and
, might contribute to the clinical phenotype.
Osteogenesis imperfecta/Ehlers−Danlos (OI/EDS) overlap syndrome is a recently described disorder of connective tissue, characterized by mutation of COL1A1 (17q21.33) or COL1A2 (7q21.3) genes, that ...are involved in α-1 and α-2 chains of type 1 collagen synthesis. The clinical spectrum of this new clinical entity is broad: patients could present a mixed phenotype that includes features of both osteogenesis imperfecta (bone fragility, long bone fractures, blue sclerae, short stature) and Ehlers−Danlos syndrome (joint hyperextensibility, soft and hyperextensible skin, abnormal wound healing, easy bruising, vascular fragility). We reported the case of a young Caucasian girl with severe short stature and a previous history of neuroblastoma, who displayed the compound phenotype of OI/EDS. Next generation sequencing was applied to the proband and her parent genome. Our patient presented a de novo heterozygous COL1A1 variant (c.3235G>A, p.Gly1079Ser), whose presence might be indicative of diagnosis of OI/EDS overlap syndrome. We also hypothesize that the association with the previous history of neuroblastoma could be influenced by the presence of COL1A1 mutation, whose role has been already described in the behavior and progression of some cancers.
Interstitial deletions of the long arm of chromosome 12 are rare, with a dozen patients carrying a deletion in 12q21 being reported. Recently a critical region (CR) has been delimited and could be ...responsible for the more commonly described clinical features, such as developmental delay/intellectual disability, congenital genitourinary and brain malformations. Other, less frequent, clinical signs do not seem to be correlated to the proposed CR. We present seven new patients harboring non-recurrent deletions ranging from 1 to 18.5 Mb differentially scattered across 12q21. Alongside more common clinical signs, some patients have rarer features such as heart defects, hearing loss, hypotonia and dysmorphisms. The correlation of haploinsufficiency of genes outside the CR to specific signs contributes to our knowledge of the effect of the deletion of this gene-poor region of chromosome 12q. This work underlines the still important role of copy number variations in the diagnostic setting of syndromic patients and the positive reflection on management and family genetic counseling.
Located contiguously on the long arm of the second chromosome are gene paralogs encoding the immunoglobulin-family co-activation receptors CD28 and cytotoxic T-lymphocyte-associated protein 4 ...(CTLA4). CD28 and CTLA4 share the same B7 ligands yet each provides opposing proliferative signals to T cells. Herein, we describe for the first time two unrelated subjects with coexisting CD28 and CTLA4 haploinsufficiency due to heterozygous microdeletions of chromosome 2q. Although their clinical phenotype, multi-organ inflammatory disease, is superficially similar to that of CTLA4 haploinsufficient autoimmune lymphoproliferative syndrome type V (ALPS5) patients, we demonstrate our subjects' underlying immunopathology to be distinct. Unlike ALPS5 T cells which hyperproliferate to T-cell receptor-mediated activation and infiltrate organs, T cells from our subjects are hypoproliferative and do not. Instead of T cell infiltrates, biopsies of affected subject tissues demonstrated infiltrates of lineage negative lymphoid cells. This histologic feature correlated with significant increases in circulating type 3 innate lymphoid cells (ILC3s) and ILC3 cytokines, interleukin 22, and interleukin-17A. CTLA4-Ig monotherapy, which we trialed in one subject, was remarkably effective in controlling inflammatory diseases, normalizing ILC3 frequencies, and reducing ILC3 cytokine concentrations.
Cardio-facio-cutaneous syndrome (CFCS) is a rare disease characterized by mental retardation, facial dysmorphisms, ectodermal abnormalities, heart defects and developmental delay. CFCS is genetically ...heterogeneous and mutations in the KRAS, BRAF, MAP2K1 (MEK1) and MAP2K2 (MEK2) genes, encoding for components of the RAS-mitogen activated protein kinase (MAPK) signaling pathway, have been identified in up to 90% of cases. Here we screened a cohort of 33 individuals with CFCS for MEK1 and MEK2 gene mutations to further explore their molecular spectrum in this disorder, and to analyze genotype-phenotype correlations. Three MEK1 and two MEK2 mutations were detected in six patients. Two missense MEK1 (L42F and Y130H) changes and one in-frame MEK2 (K63_E66del) deletion had not been reported earlier. All mutations were localized within exon 2 or 3. Together with the available records, the present data document that MEK1 mutations are relatively more frequent than those in MEK2, with exons 2 and 3 being mutational hot spots in both genes. Mutational analysis of the affected MEK1 and MEK2 exons did not reveal occurrence of mutations among 75 patients with Noonan syndrome, confirming the low prevalence of MEK gene defects in this disorder. Clinical review of known individuals with MEK1/MEK2 mutations suggests that these patients show dysmorphic features, ectodermal abnormalities and cognitive deficit similar to what was observed in BRAF-mutated patients and in the general CFCS population. Conversely, congenital heart defects, particularly mitral valve and septal defects, and ocular anomalies seem to be less frequent among MEK1/MEK2 mutation-positive patients.
Background
Since the establishment of chromosomal microarrays in clinical practice, many new microdeletion/microduplication syndromes have been identified, including 18q11.2 microdeletion. Chromosome ...18q deletion syndrome is commonly classified into distal deletion and a much rarer proximal interstitial deletion spanning the 18q11.2‐q21.1 region.
Methods
We report two new patients and review 27 additional cases in DECIPHER/ClinGen databases and four cases from the literature, with more proximal 18q deletions involving 18q11‐q12 (band 1 only; 17.2–43.5 Mb position) deletion.
Results
Common presentations of 18q11‐q12 deletions include developmental delay/intellectual disability (DD/ID) (82%); speech delay/autism/attention deficit and hyperactivity/other behavioral problems (30%); conotruncal heart defects (15%); and subtle/non‐specific facial dysmorphism. The deletion in four out of five cases with cardiac defect was distal to GATA6, suggesting an alternative mechanism other than haploinsufficiency of GATA6 as an underlying cause of cardiac malformations. Precocious puberty with advanced skeletal age was first observed in one patient, suggesting a unique and expanded phenotype of proximal 18q deletion. When comparing genotype–phenotype correlations from the present study with previous reports, the critical regions for selected phenotypes of 18q11‐q12 deletion syndrome could be narrowed down as follows: 38.8–43.5 Mb for moderate to severe DD/ID, 19.6–24.4 Mb and 26.9–28.6 Mb for conotruncal heart defect.
Conclusion
The detailed clinical delineation of the proximal 18q deletions identified in this study should contribute to better understanding of the genotype–phenotype correlations and better long‐term care of patients with this rare syndrome.
We report two new patients of proximal 18q11‐q12 microdeletion syndrome and review 27 additional cases in DECIPHER/ClinGen databases and four cases from the literature about these proximal deletions.
Genetic syndromes represent relevant and rare diseases. These conditions include a large amount of epidemiological, pathogenetic and clinical features. However, a systematic approach to genetic ...syndromes is often prevented by the rareness of these diseases. So, although clinical features are usually precisely defined, nowadays more uncommon associations between genetic syndromes and internal medicine related diseases have been insufficiently studied. Autoimmune hepatitis (AIH) is a chronic liver disease caused by loss of tolerance to hepatocyte-specific auto-antigens. Conversely, a better knowledge about specific genetic syndromes in which AIH is more frequent could be important in the clinical management of patients, both for an early diagnosis and for a prompt therapy. Furthermore, a systematic approach could explain if onset, clinical course, and response to treatment of AIH are typical for specific genetic syndromes. We took in consideration all the scientific articles reported in PubMed in the last 10 years, from 2010 to 2020. The purpose of this review is to explore the prevalence of AIH in genetic syndrome, but also to suggest new classification, that could be useful for pathogenetic hypothesis and clinical approach to genetic syndrome. From the 139 publications selected using keywords “autoimmune hepatitis” and “genetic syndrome”, 30 papers (21.6%) respected the chosen inclusion criteria, reporting the association between AIH in patients with a genetic syndrome. We have collected in all 47 patients with AIH and genetic syndrome, and with median age of 12.6-year-old. We suggest that when a patient presents a clinical picture of cryptogenic chronic hepatitis, that is unexplained, it is useful to explore differential diagnosis of AIH associated with genetic syndrome. Given the clinical relevance of this topic, further reports are needed to demonstrate our hypothesis and collect new evidence in this field.
Joubert syndrome (JBTS) is a rare autosomal recessive disorder with an underestimated prevalence due to lack of recognition of clinical signs or failure to diagnose this pathology. JBTS is clinically ...heterogeneous, and it is characterized by a multiple organ involvement predominantly due to the requirement for Joubert gene function in several tissues. Renal disease affects approximately 30% of patients with JBTS, presenting itself in most cases as nephronophthisis (NPHP), a structural tubulo-interstitial disorder characterized by thickened basal membrane of the tubular epithelium and progressive interstitial fibrosis, associated with cysts at the cortico-medullary junction. We propose three cases concerning three patients with JBTS having different years of illness and degrees of renal impairment, evaluating the parameters of renal function at the time of genetic diagnosis and seen after a follow-up of 7 years. We measured neutrophil gelatinase-associated lipocalin (NGAL), considered as an excellent predictor of kidney injury, to evaluate whether this biomarker might be an early biomarker for JBTS-related kidney disease. NGAL was high in all three cases, but with different levels, indicating a tubular suffering typical of this syndrome, with dissimilar severity in the analyzed subjects. NGAL could represent an early indicator of renal damage useful to start an intensive nephrologic follow-up.
Miscarriage is a condition that affects 10%–15% of all clinically recognized pregnancies, most of which occur in the first trimester. Approximately 50% of first‐trimester miscarriages result from ...fetal chromosome abnormalities.
Conventional karyotyping analysis is limited due to unsuccessful culture fetal tissue and poor chromosome quality.
Chromosomal microarray analysis (CMA) provides a significant increase in test success rate and incremental diagnostic yield in early pregnancy loss, using fetal DNA.
We aimed to estimate detection of pathogenic Copy Number Variants (CNVs) and variants of uncertain significance (VOUS) in early pregnancy losses. Moreover we integrate cytogenomic findings performing Whole Exome Sequencing (WES) in order to elucidate the genetic associations of gene variants clinically significant for the viability of a conceptus.
We collected product of conception (POC) samples (n= 33), managed in our genetic unit between February 1, 2020, and July 31, 2021.
Fetal tissue samples were obtained after informed consent from females of average age 37 years old, who experienced spontaneous pregnancy losses (□<20 weeks) (70%), medical abortion (9%) and miscarriage after assisted reproductive treatment (21%).
In the 97% of cases, the cytogenomic and/or molecular analysis were performed and concluded with an informative results (n= 32) useful for couple counseling.
To avoid risk of maternal cell contamination and to define sex chromosomes, before CMA, QF‐PCR was performed.
As aspected, autosomal trisomies are shown to be the most frequent anomalies (42%) associated with first‐trimester miscarriage, followed by monosomy X (3%). 2 CNVs, are detected (6%): 1 pathogenic de novo deletion associated with monosomy 1pter and 1 duplication with uncertain clinical significance in region 7q21.13, segregated from healthy father.
In this sample, we performed WES in order to understand the possible genetic cause of major malformations detected by ultrasound exploration. A missense variant in ITF80 gene was detected. The encoded protein is essential for the development and maintenance of primary cilia, but a single variant, inherited from father, is not enough to conclude the diagnosis. In another case, with a fetal peculiar clinical picture, the WES analysis performed, showed a compound heterozygosity in the CC2D2A gene, associated with Meckel syndrome, an autosomal recessive ciliopathy. Ciliopathies are an expanding disease spectrum that have been associated with over 40 genes to date. In this case, the genetic diagnosis allow us to determine the cause of miscarriage with a major impact on the future couple reproductive plans and prenatal care in future pregnancies.
This study demonstrates that the DNA‐based CMA technology overcomes many of the limitations of routine cytogenetic analysis of POC samples and, in selected cases, integration with WES analysis increase diagnostic rate and recurrence‐risk for subsequent pregnancies can be also determined.
Stargardt disease (STGD) is the most common form of inherited juvenile macular degeneration. It is inherited as autosomal recessive trait (STGD1), although STGD3 and STGD4 are inherited as autosomal ...dominant inheritance pattern. STGD3 is caused by mutations in the elongation of very long-chain fatty acids-like 4 (ELOVL4) gene encoding for a very long-chain fatty acid elongase. Mutations lead to a truncated Elovl4, lacking of a dilysine motif necessary for retention of transmembrane proteins in the endoplasmic reticulum. STGD occurs due to altered synthesis of very long-chain polyunsaturated fatty acids (VLC-PUFA). Our work investigates the role of two variants in the ELOVL4 gene promoter region, c.-236 C>T (rs240307) and c.-90 G>C (rs62407622), identified in a patient with STGD in transconfiguration.
Their effects on ELOVL4 expression were examined by Dual-Luciferase Reporter assay.
rs62407622 and rs240307 variants caused 14% and 18% of expression reduction, respectively, compared with wild-type promoter. A very strong decreased gene expression was caused by coexistence of both variants.
A highly reduced activity of the ELOVL4 promoter was registered due to combination of two variants. Decrease of ELOVL4 enzymatic activity could lead to a deficiency of VLC-PUFA, essential components for rods function and longevity, which are among the parameters involved in the etiopathogenesis of STGD.
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