Teresa Palladino

3p14.1 de novo microdeletion involving the FOXP1 gene in an adult patient with autism, severe speech delay and deficit of motor coordination

Interstitial deletion of chromosome region 3p14.1, including FOXP1 gene, is relatively rare and, until recently, there were no strong evidences to support the hypothesis that this microdeletion could play a role in the etiology of genomic disorders. Here, we report on an adult patient with a recognizable phenotype of autism, severe speech delay, deficit of motor coordination and typical dysmorphic features. Analysis of a dense whole genome single-nucleotide polymorphism (SNP) array showed a 1Mb interstitial deletion of chromosome region 3p14.1 including the entire coding region of FOXP1 (MIM 605515) gene. In order to study the parental origin of the deletion, we analyzed selected SNPs in the deleted area in the proband and his parents showing Mendelian incompatibilities suggesting a de novo deletion on the chromosome of paternal origin. Despite the frequency of this genomic alteration has not been estimated, our patient confirm the hypothesis that microdeletion of 3p14.1 seems to be a rare cause of cognitive disorders and that haploinsufficiency of FOXP1 may play a role in neurological and language deficits in patients carrying a 3p14.1 deletion. Finally, our patient is also important because useful to further delineate the clinical spectrum secondary to the 3p14.1 microdeletions.

Hearing loss features in GJB2 biallelic mutations and GJB2/GJB6 digenic inheritance in a large Italian cohort

The aim of this study was to describe the clinical features of hearing loss due to mutations on connexin 26/30 coding genes (GJB2/GJB6). Mutations in the GJB2 gene are found to account for approximately 50% of cases of autosomal recessive non-syndromic deafness. Several European studies have estimated that the GJB2 healthy carrier condition involves about 2–4% of the population, with the 35delG mutations being the most common. A 342-kb deletion truncating the GJB6 gene (encoding connexin-30) has been associated with autosomal recessive non-syndromic deafness, mostly as digenic inheritance of the Cx30 deletion/Cx26 mutation. The following retrospective study describes audiological features and genotypes of a large cohort of 376 Italian hearing-impaired patients who underwent genetic screening for the GJB2/GJB6 genes and received follow-up care at our centre between January 2002 and October 2006. Sixteen different genotypes causing deafness in more than 27% of patients with either biallelic mutations or digenic inheritance GJB2/GJB6 were identified. The most frequent mutations were 35delG, M34T, L90P, and R184P.

A novel deletion in 2q24.1q24.2 in a girl with mental retardation and generalized hypotonia: a case report

BackgroundChromosomal imbalances, recognized as the major cause of mental retardation, are often due to submicroscopic deletions or duplications not evidenced by conventional cytogenetic methods. To date, interstitial deletion of long arm of chromosome 2 have been reported for more than 100 cases, although studies reporting small interstitial deletions involving the 2q24.1q24.2 region are rare. With the widespread clinical use of comparative genomic hybridization chromosomal microarray technology, several cryptic chromosome imbalances have outlined new genotype-phenotype correlations and isolated a number of distinctive clinical conditions.Resultshere we report on a girl with mental retardation and generalized hypotonia. A genome-wide screen for copy number variations (CNVs) using single nucleotide polymorphisms (SNPs) array revealed a 7.5 Mb interstitial deletion of chromosome region 2q24.1q24.2 encompassing 59 genes, which was absent in parents. The gene content analysis of the deleted region and review of the literature revealed the presence of some genes that may be indicated as good candidate in generating the main clinical features of the patient.Discussionthe present case represents a further patient described in the literature with an interstitial deletion of chromosome 2q24.1q24.2. Our patient shares some clinical features with the previously reported patients carriers of overlapping 2q24 deletion. Although more cases are needed to delineate the full-blown phenotype of 2q24.1q24.2 deletion syndrome, published data and present observation suggest that hemizygosity of this region results in a clinically recognizable phenotype. Considering these clinical and cytogenetic similarities, we suggest the existence of an emerging syndrome associated to 2q24.1q24.2 region.

An emerging phenotype of interstitial 15q25.2 microdeletions: clinical report and review.

Interstitial deletions of chromosome 15q25.2 are rare. To date, only nine patients with microdeletions within this chromosomal region have been described. Here, we report on a girl with severe speech and psychomotor delay, behavioral problems and mild dysmorphic features with a 1.6 Mb deletion in 15q25.2 region. In order to study the parental origin of the rearrangement, we analyzed selected SNPs in the deleted area in the patient and her parents, showing Mendelian incompatibilities suggesting a de novo deletion on the chromosome of maternal origin. By comparing the clinical and molecular features of our patient with five previously reported cases of an overlapping deletion, we suggest that 15q25.2 deletion is an emerging syndrome characterized by a distinct although variable spectrum of clinical manifestations, including mild dysmorphic features, neurodevelopmental delay, and a recognizable pattern of congenital malformation. Furthermore, our patient is the second one in which a behavioral phenotype characterized by hyperactivity, anxiety, and autistic features was reported, indicating that these features might be part of this new syndromic condition. Breakpoints of the deletion in the patient reported here are useful to better define the smallest region of overlap (SRO) among all the patients. Selected genes that are present in the hemizygous state and which might be important for the phenotype of these patients, are discussed in context of the clinical features. In conclusion, our patient increases the knowledge about the molecular and phenotypic consequences of interstitial 15q25.2 deletions, highlighting that deletions of this region may be responsible for a new microdeletion syndrome.

Microdeletion of 12q24.31: Report of a girl with intellectual disability, stereotypies, seizures and facial dysmorphisms

We provide a detailed clinical and molecular characterization of an 11‐year‐old female patient presenting with neurodevelopmental delay (NDD), intellectual disability (ID), seizures, stereotypies and dysmorphic features. Chromosomal microarrays analysis (CMA) detected a small, rare de novo deletion on chromosome 12q24.31 encompassing 31 protein‐coding RefSeq genes and a microRNA. Phenotypic comparison with molecularly well‐defined cases previously reported in the literature harboring an overlapping 12q24.31 microdeletion indicate that these patients shared common clinical features including neurodevelopmental delay, intellectual disability and behavioral problems. Also, seizures and dysmorphic features are frequent and a consistent pattern was recognized. Since there are remarkable resemblance between the patient described here and at least another one previously reported, our report is provides supportive evidence for the existence of an emerging syndrome caused by a microdeletion in 12q24.31. We propose a minimal region shared among patients contributing to the etiology of the common clinical features observed suggesting as candidate, for the first time, the gene SETD1B which is a component of a histone methyltransferase complex. In addition, we speculate on the possible contributive role of the MIR4304 to some clinical features observed in our patient. Evaluation of more patients with well‐characterized deletions within 12q24.31, as well as careful clinical assessment of them, is needed to corroborate our hypothesis, to perform a more detailed genotype‐phenotype correlation and, finally, to fully delineate this emerging microdeletion syndrome.

8q12.1q12.3 de novo microdeletion involving the CHD7 gene in a patient without the major features of CHARGE syndrome: Case report and critical review of the literature

CHARGE syndrome is an autosomal dominant inherited disorder characterized by a specific and recognizable pattern of anomalies. De novo mutations or deletions of the gene encoding chromodomain helicase DNA binding protein 7 (CHD7) are the major cause of CHARGE syndrome. In this report, we describe a patient with a typical phenotype characterized by psychomotor retardation, hypertrichosis, facial asymmetry, synophria, failure to thrive, developmental delay and gastro-esophageal reflux, carrying a de novo 6.04Mb interstitial deletion in 8q12.1q12.3 detected by single nucleotide polymorphism (SNP) array analysis. Despite the deletion includes CHD7 and although the patient shares some of the clinical features of the CHARGE syndrome, she does not fulfill the clinical criteria for this syndrome. To the best of our knowledge, this is the second case with an entire deletion of the CHD7 gene not leading to CHARGE syndrome and, for this reason, useful to expand and further delineate the clinical features associated with the 8q12.1q12.3 deletion. Furthermore, the literature review revealed that the phenotype secondary to duplications of the same region partially overlaps with the phenotype reported in this study. Selected genes that are present in the hemizygous state and which might be important for the phenotype of this patient, are discussed in context of the clinical features.

Identification of a novel mutation in the SLC26A4 gene in an Italian with fluctuating sensorineural hearing loss

Pendred syndrome is an autosomal recessive disorder characterized by congenital sensorineural deafness, goitre and defective iodide organification. Congenital and profound hearing loss is the hallmark of the syndrome, while goitre and thyroid dysfunction are highly variable even within the same family. Clinical features are due to altered formation of pendrin, a chloride/iodide transporter protein expressed in the inner ear, thyroid gland and kidney. A novel substitution was found in exon 7 of the pendrin encoding gene (SLC26A4) that leads to a stop codon, S314X. The new variation was found in compound heterozygosity with L445W mutation in a hearing impaired patient with bilateral Mondinis dysplasia and goitre.

Calcium-sensing-related gene mutations in hypercalcaemic hypocalciuric patients as differential diagnosis from primary hyperparathyroidism: detection of two novel inactivating mutations in an Italian population

BACKGROUND Inactivating mutations of the calcium-sensing receptor (CaSR), of the G-protein subunit α11 (GNA11) and of the adaptor-related protein complex 2, sigma 1 subunit (AP2S1) genes are responsible for familial hypocalciuric hypercalcaemia (FHH). The aim of this study was to analyse prevalence and pathogenicity of CaSR, GNA11 and AP2S1 mutations in patients with an FHH phenotype and to compare them with a sample of patients with primary hyperparathyroidism (PHPT) in order to identify the most useful laboratory parameter for a differential diagnosis. METHODS Patients with an FHH phenotype were studied with polymerase chain reaction amplification and direct sequencing of the entire CaSR, GNA11 and AP2S1 coding sequences. Novel mutations were introduced in a Myc-tagged human wild-type (WT) CaSR cDNA-expressing vector, and functional assay was performed on human embryonic kidney cells evaluating expression and function of mutated proteins. RESULTS Among 16 FHH patients, none had an inactivating GNA11 or AP2S1 mutation while 3 (18.8%) carried a CaSR mutation and 10 (62.5%) at least one CaSR polymorphism. Within the latter group, 7 of 10 patients had more than one polymorphism (4.1 ± 2.1 per patient). Two novel CaSR mutations [c.2120A>T (E707V) and c.2320G>A (G774S)] were identified: the E707V mutation prevented CaSR expression (western blot), whereas the G774S mutation determined a reduced receptor sensitivity to calcium (IP3 assay). PHPT patients showed significantly (P < 0.001) higher serum calcium, parathyroid hormone, urinary calcium and calcium-creatinine clearance ratio (CCCR) and significantly lower serum phosphate than FHH ones. CONCLUSIONS FHH should be clearly differentiated by PHPT to avoid unnecessary surgery: CCCR could be a useful screening tool while genetic analysis should include the two novel CaSR mutations herein described. The role of multiple polymorphisms deserves further investigation in patients with an FHH phenotype.

A novel missense mutation in the Connexin 26 gene associated with autosomal recessive nonsyndromic sensorineural hearing loss in a consanguineous Tunisian family

Nonsyndromic sensorineural hearing impairment is inherited in a predominantly autosomal recessive manner in up to 70% of cases. The gene more often involved is GJB2, encoding the gap junction protein Connexin 26. We report here a novel missense mutation in the GJB2 gene found in a Tunisian family. A homozygous change C/G at nucleotide 263 was detected in the 4-year-old girl of this family, affected by congenital moderate hearing loss. This transversion leads to the replacement of a highly conserved alanine with glycine at codon 88 (A88G). The consanguineous parents of the child are healthy carriers of the mutation.

Putative TMPRSS3/GJB2 digenic inheritance of hearing loss detected by targeted resequencing

The paper describes a putative digenic form of deafness in two siblings affected by non-syndromic hereditary hearing loss, detected by a Targeted resequencing approach. Given that a previous paper suggested TMPRSS3 and GJB2 genes as responsible for a digenic form of hearing loss, our data support and reinforce this hypothesis.