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1.  Further analysis of previously implicated linkage regions for Alzheimer's disease in affected relative pairs 
BMC Medical Genetics  2009;10:122.
Genome-wide linkage studies for Alzheimer's disease have implicated several chromosomal regions as potential loci for susceptibility genes.
In the present study, we have combined a selection of affected relative pairs (ARPs) from the UK and the USA included in a previous linkage study by Myers et al. (Am J Med Genet, 2002), with ARPs from Sweden and Washington University. In this total sample collection of 397 ARPs, we have analyzed linkage to chromosomes 1, 9, 10, 12, 19 and 21, implicated in the previous scan.
The analysis revealed that linkage to chromosome 19q13 close to the APOE locus increased considerably as compared to the earlier scan. However, linkage to chromosome 10q21, which provided the strongest linkage in the previous scan could not be detected.
The present investigation provides yet further evidence that 19q13 is the only chromosomal region consistently linked to Alzheimer's disease.
PMCID: PMC2791756  PMID: 19951422
2.  Factor VII deficiency and developmental abnormalities in a patient with partial monosomy of 13q and trisomy of 16p: case report and review of the literature 
Unbalanced chromosomal translocations may present with a variety of clinical and laboratory findings and provide insight into the functions of genes on the involved chromosomal segments.
Case Presentation
A 9 year-old boy presented to our clinic with Factor VII deficiency, microcephaly, a seizure disorder, multiple midline abnormalities (agenesis of the corpus callosum, imperforate anus, bilateral optic nerve hypoplasia), developmental delay, hypopigmented macules, short 5th fingers, and sleep apnea due to enlarged tonsils. Cytogenetic and fluorescence in situ hybridization analyses revealed an unbalanced translocation involving the segment distal to 16p13 replacing the segment distal to 13q33 [46, XY, der(13)t(13;16)(q33;p13.3)]. Specific BAC-probes were used to confirm the extent of the 13q deletion.
This unique unbalanced chromosomal translocation may provide insights into genes important in midline development and underscores the previously-reported phenotype of Factor VII deficiency in 13q deletions.
PMCID: PMC1379634  PMID: 16412230
3.  Pathogenesis of vestibular schwannoma in ring chromosome 22 
BMC Medical Genetics  2009;10:97.
Ring chromosome 22 is a rare human constitutional cytogenetic abnormality. Clinical features of neurofibromatosis type 1 and 2 as well as different tumour types have been reported in patients with ring chromosome 22. The pathogenesis of these tumours is not always clear yet.
We report on a female patient with a ring chromosome 22 presenting with severe mental retardation, autistic behaviour, café-au-lait macules and facial dysmorphism. Peripheral blood lymphocytes were karyotyped and array CGH was performed on extracted DNA. At the age of 20 years she was diagnosed with a unilateral vestibular schwannoma. Tumour cells were analyzed by karyotyping, array CGH and NF2 mutation analysis.
Karyotype on peripheral blood lymphocytes revealed a ring chromosome 22 in all analyzed cells. A 1 Mb array CGH experiment on peripheral blood DNA showed a deletion of 5 terminal clones on the long arm of chromosome 22. Genetic analysis of vestibular schwannoma tissue revealed loss of the ring chromosome 22 and a somatic second hit in the NF2 gene on the remaining chromosome 22.
We conclude that tumours can arise by the combination of loss of the ring chromosome and a pathogenic NF2 mutation on the remaining chromosome 22 in patients with ring chromosome 22. Our findings indicate that patients with a ring 22 should be monitored for NF2-related tumours starting in adolescence.
PMCID: PMC2758865  PMID: 19772601
4.  No evidence for the association of DRD4 with ADHD in a Taiwanese population within-family study 
BMC Medical Genetics  2005;6:31.
Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent and highly heritable childhood disorder. The dopamine D4 receptor (DRD4) gene has shown a genetic association with ADHD in Caucasian populations with meta-analysis indicating a small but significant effect across datasets. It remains uncertain whether this association can be generalised to non-Caucasian ethnic groups. Here we investigate two markers within the DRD4 gene in a Taiwanese population, the exon 3 variable number tandem repeat (VNTR) and a 5' 120 base-pair duplication.
Within-family transmission disequilibrium tests of association of the 5' 120 base-pair duplication, and exon 3 VNTR in a Taiwanese population.
No evidence of association of ADHD with either polymorphism in this population was observed.
The DRD4 gene markers investigated were not found to be associated with ADHD in this Taiwanese sample. Further work in Taiwanese and other Asian populations will therefore be required to establish whether the reports of association of DRD4 genetic variants in Caucasian samples can be generalised to Asian populations.
PMCID: PMC1236928  PMID: 16143039
5.  Discontinuous microduplications at chromosome 10q24.31 identified in a Chinese family with split hand and foot malformation 
BMC Medical Genetics  2013;14:45.
Split hand/foot malformation (SHFM) is a congenital disorder characterized by a cleft of the hands and/or feet due to dificiency of central rays. Genomic rearrangement at 10q24 has been found to cause nonsyndromic SHFM (SHFM3).
Four patients and fourteen unaffected individuals from a four-generation Chinese pedigree with typical SHFM3 phenotypes were recruited for this study. After informed consent was obtained, genome-wide copy number analysis was performed on all patients and two normal family members using the Affymetrix Cytogenetics Whole-Genome 2.7M Array. The results were then confirmed by real-time quantitative polymerase chain reaction in all available individuals of this pedigree. Candidate genes were further screened for mutation through sequence analyses.
Copy number analysis showed a microduplication at chromosome 10q24.31-q24.32 co-segregating with the SHFM phenotype. Compared to other known genomic duplications for SHFM3, the duplication described here contains two discontinuous DNA fragments. The minimal centromeric duplicated segment of 259 kb involves LBX1, POLL and a disrupted BTRC. The minimal telomeric duplication of 114 kb encompasses DPCD and one part of FBXW4. No coding and splice-site mutations of candidate genes in the region were found.
Genomic duplications at chromosome 10q24.3, which were identified in the current study, provide further evidence for limb-specific cis-regulatory sequences in this region, highlighting the importance of chromosome 10q24.31-q24.32 in limb development and SHFM pathogenesis.
PMCID: PMC3637097  PMID: 23596994
SHFM; Microduplication; Han Chinese
6.  Novel cAMP binding protein-BP (CREBBP) mutation in a girl with Rubinstein-Taybi syndrome, GH deficiency, Arnold Chiari malformation and pituitary hypoplasia 
BMC Medical Genetics  2013;14:28.
Rubinstein-Taybi syndrome (RTS) is a rare autosomal dominant disorder (prevalence 1:125,000) characterised by broad thumbs and halluces, facial dysmorphism, psychomotor development delay, skeletal defects, abnormalities in the posterior fossa and short stature. The known genetic causes are point mutations or deletions of the cAMP-response element binding protein-BP (CREBBP) (50-60% of the cases) and of the homologous gene E1A-binding protein (EP300) (5%).
Case presentation
We describe, for the first time in literature, a RTS Caucasian girl, 14-year-old, with growth hormone (GH) deficiency, pituitary hypoplasia, Arnold Chiari malformation type 1, double syringomyelic cavity and a novel CREBBP mutation (c.3546insCC).
We hypothesize that CREBBP mutation we have identified in this patient could be responsible also for RTS atypical features as GH deficiency and pituitary hypoplasia.
PMCID: PMC3598247  PMID: 23432975
Rubinstein-Taybi syndrome; GH deficiency; Arnold Chiari malformation; Syrinx; Pituitary hypoplasia
7.  A 4q35.2 subtelomeric deletion identified in a screen of patients with co-morbid psychiatric illness and mental retardation 
BMC Medical Genetics  2004;5:21.
Cryptic structural abnormalities within the subtelomeric regions of chromosomes have been the focus of much recent research because of their discovery in a percentage of people with mental retardation (UK terminology: learning disability). These studies focused on subjects (largely children) with various severities of intellectual impairment with or without additional physical clinical features such as dysmorphisms. However it is well established that prevalence of schizophrenia is around three times greater in those with mild mental retardation. The rates of bipolar disorder and major depressive disorder have also been reported as increased in people with mental retardation. We describe here a screen for telomeric abnormalities in a cohort of 69 patients in which mental retardation co-exists with severe psychiatric illness.
We have applied two techniques, subtelomeric fluorescence in situ hybridisation (FISH) and multiplex amplifiable probe hybridisation (MAPH) to detect abnormalities in the patient group.
A subtelomeric deletion was discovered involving loss of 4q in a patient with co-morbid schizoaffective disorder and mental retardation.
The precise region of loss has been defined allowing us to identify genes that may contribute to the clinical phenotype through hemizygosity. Interestingly, the region of 4q loss exactly matches that linked to bipolar affective disorder in a large multiply affected Australian kindred.
PMCID: PMC515177  PMID: 15310400
8.  Identification of a rare 17p13.3 duplication including the BHLHA9 and YWHAE genes in a family with developmental delay and behavioural problems 
BMC Medical Genetics  2012;13:93.
Deletions and duplications of the PAFAH1B1 and YWHAE genes in 17p13.3 are associated with different clinical phenotypes. In particular, deletion of PAFAH1B1 causes isolated lissencephaly while deletions involving both PAFAH1B1 and YWHAE cause Miller-Dieker syndrome. Isolated duplications of PAFAH1B1 have been associated with mild developmental delay and hypotonia, while isolated duplications of YWHAE have been associated with autism. In particular, different dysmorphic features associated with PAFAH1B1 or YWHAE duplication have suggested the need to classify the patient clinical features in two groups according to which gene is involved in the chromosomal duplication.
We analyze the proband and his family by classical cytogenetic and array-CGH analyses. The putative rearrangement was confirmed by fluorescence in situ hybridization.
We have identified a family segregating a 17p13.3 duplication extending 329.5 kilobases by FISH and array-CGH involving the YWHAE gene, but not PAFAH1B1, affected by a mild dysmorphic phenotype with associated autism and mental retardation. We propose that BHLHA9, YWHAE, and CRK genes contribute to the phenotype of our patient. The small chromosomal duplication was inherited from his mother who was affected by a bipolar and borderline disorder and was alcohol addicted.
We report an additional familial case of small 17p13.3 chromosomal duplication including only BHLHA9, YWHAE, and CRK genes. Our observation and further cases with similar microduplications are expected to be diagnosed, and will help better characterise the clinical spectrum of phenotypes associated with 17p13.3 microduplications.
PMCID: PMC3495055  PMID: 23035971
Familial 17p13.3 duplication syndrome; PAFAH1B1 and YWHAE genes; Array-CGH
9.  Left ventricular hypertrabeculation/noncompaction with epilepsy, other heart defects, minor facial anomalies and new copy number variants 
BMC Medical Genetics  2012;13:60.
Left ventricular hypertrabeculation/noncompaction (LVHT) is a cardiac abnormality of unknown etiology which has been described in children as well as in adults with and without chromosomal aberrations. LVHT has been reported in association with various cardiac and extracardiac abnormalities like epilepsy and facial dysmorphism.
Case presentation
A unique combination of LVHT, atrial septal defect, pulmonary valve stenosis, aortic stenosis, epilepsy and minor facial anomalies is presented in a 5.5 years old girl. Microarray-based genomic hybridization (array-CGH) detected six previously not described copy number variants (CNVs) inherited from a clinically unaffected father and minimally affected mother, thus, most likely, not clinically significant but rare benign variants.
Despite this complex phenotype de novo microdeletions or microduplications were not detected by array CGH. Further investigations, such as whole exome sequencing, could reveal point mutations and small indels as the possible cause.
PMCID: PMC3490829  PMID: 22830313
Cardiomyopathy; Congenital heart disease; Neurology; Pediatrics; Array CGH; Hypertrabeculation; Seizures
10.  A de novo marker chromosome derived from 9p in a patient with 9p partial duplication syndrome and autism features: genotype-phenotype correlation 
BMC Medical Genetics  2010;11:135.
Previous studies focusing on candidate genes and chromosomal regions identified several copy number variations (CNVs) associated with increased risk of autism or autism spectrum disorders (ASD).
Case Presentation
We describe a 17-year-old girl with autism, severe mental retardation, epilepsy, and partial 9p duplication syndrome features in whom GTG-banded chromosome analysis revealed a female karyotype with a marker chromosome in 69% of analyzed metaphases. Array CGH analysis showed that the marker chromosome originated from 9p24.3 to 9p13.1 with a gain of 38.9 Mb. This mosaic 9p duplication was detected only in the proband and not in the parents, her four unaffected siblings, or 258 ethnic controls. Apart from the marker chromosome, no other copy number variations (CNVs) were detected in the patient or her family. Detailed analysis of the duplicated region revealed: i) an area extending from 9p22.3 to 9p22.2 that was previously identified as a critical region for the 9p duplication syndrome; ii) a region extending from 9p22.1 to 9p13.1 that was previously reported to be duplicated in a normal individual; and iii) a potential ASD locus extending from 9p24.3 to 9p23. The ASD candidate locus contained 34 genes that may contribute to the autistic features in this patient.
We identified a potential ASD locus (9p24.3 to 9p23) that may encompass gene(s) contributing to autism or ASD.
PMCID: PMC2946294  PMID: 20858261
11.  Cardiac conduction abnormalities and congenital immunodeficiency in a child with Kabuki syndrome: Case report 
BMC Medical Genetics  2005;6:28.
Since it's recognition in 1981, a more complete phenotype of Kabuki syndrome is becoming evident as additional cases are identified. Congenital heart defects and a number of visceral abnormalities have been added to the typical dysmorphic features originally described.
Case Report
In this report we describe the clinical course of a child diagnosed with Kabuki syndrome based on characteristic clinical, radiological and morphologic features who died of a cardiac arrhythmia at 11-months of age. This infant, however, had abnormal pulmonary architecture and alterations in his cardiac conduction system resulting in episodes of bradycardia and asystole. This child also had an immunological phenotype consistent with common variable immunodeficiency. His clinical course consisted of numerous hospitalizations for recurrent bacterial infections and congenital hypogammaglobulinemia characterized by low serum IgG and IgA but normal IgM levels, and decreased antibody levels to immunizations. T-, B- and NK lymphocyte subpopulations and T-cell function studies were normal.
This child may represent a more severe phenotype of Kabuki syndrome. Recurrent infections in a child should prompt a thorough immunological evaluation. Additionally, electrophysiology testing may be indicated if cardiopulmonary events occur which are not explained by anatomic defects.
PMCID: PMC1190177  PMID: 16042804
12.  A combined targeted mutation analysis of IRF6 gene would be useful in the first screening of oral facial clefts 
BMC Medical Genetics  2013;14:37.
Interferon Regulatory Factor 6 (IRF6) is a member of the IRF family of transcription factors. It has been suggested to be an important contributor to orofacial development since mutations of the IRF6 gene has been found in Van der Woude (VWS) and popliteal pterygium syndromes (PPS), two disorders that can present with isolated cleft lip and palate. The association between IRF6 gene and cleft lip and palate has also been independently replicated in many populations.
We screened a total of 155 Taiwanese patients with cleft lip with or without cleft palate (CL/P); 31 syndromic (including 19 VWS families), 44 non-syndromic families with at least two affected members, and 80 non-syndromic patients through a combined targeted, polymerase chain reaction (PCR)-based mutation analysis for the entire coding regions of IRF6 gene.
We found 11 mutations in 57.89% (11/19) of the VWS patients and no IRF6 mutation in 44 of the non-syndromic multiplex families and 80 non-syndromic oral cleft patients. In this IRF6 gene screening, five of these mutations (c.290 A>G, p.Tyr97Cys; c.360-375 16 bp deletion, p.Gln120HisfsX24; c.411_412 insA, p.Glu136fsX3; c.871 A>C, p.Thr291Pro; c.969 G>A, and p.Trp323X) have not been reported in the literature previously. Exon deletion was not detected in this series of IRF6 gene screening.
Our results confirm the crucial role of IRF6 in the VWS patients and further work is needed to explore for its function in the non-syndromic oral cleft with vary clinical features.
PMCID: PMC3606492  PMID: 23510002
IRF6 gene; Mutation analyses; Orofacial clefts
13.  The Framingham Heart Study, on its way to becoming the gold standard for Cardiovascular Genetic Epidemiology? 
BMC Medical Genetics  2007;8:63.
The Framingham Heart Study, founded in 1948 to examine the epidemiology of cardiovascular disease in a small town outside of Boston, has become the worldwide standard for cardiovascular epidemiology. It is among the longest running, most comprehensively characterized multi-generational studies in the world. Such seminal findings as the effects of smoking and high cholesterol on heart disease came from the Framingham Heart Study. At the time of publication these were novel cardiovascular disease (CVD) risk factors, now they are the basis of treatment and prevention in the US. Is the Framingham study now on it's way to becoming the gold standard for genetic epidemiology of CVD? Will the novel genetic findings of today become the health care standards of tomorrow? The accompanying articles summarizing the results of genome-wide association studies (GWAS) give the reader a first glimpse into the possibilities.
PMCID: PMC2151937  PMID: 17916250
14.  Familial deletion 18p syndrome: case report 
BMC Medical Genetics  2006;7:60.
Deletion 18p is a frequent deletion syndrome characterized by dysmorphic features, growth deficiencies, and mental retardation with a poorer verbal performance. Until now, five families have been described with limited clinical description. We report transmission of deletion 18p from a mother to her two daughters and review the previous cases.
Case presentation
The proband is 12 years old and has short stature, dysmorphic features and moderate mental retardation. Her sister is 9 years old and also has short stature and similar dysmorphic features. Her cognitive performance is within the borderline to mild mental retardation range. The mother also presents short stature. Psychological evaluation showed moderate mental retardation. Chromosome analysis from the sisters and their mother revealed the same chromosomal deletion: 46, XX, del(18)(p11.2). Previous familial cases were consistent regarding the transmission of mental retardation. Our family differs in this regard with variable cognitive impairment and does not display poorer verbal than non-verbal abilities. An exclusive maternal transmission is observed throughout those families. Women with del(18p) are fertile and seem to have a normal miscarriage rate.
Genetic counseling for these patients should take into account a greater range of cognitive outcome than previously reported.
PMCID: PMC1540411  PMID: 16842614
15.  Keratinocytic epidermal nevus syndrome with Schwann cell proliferation, lipomatous tumour and mosaic KRAS mutation 
BMC Medical Genetics  2015;16:6.
Keratinocytic epidermal nevus syndrome (KENS) is a complex disorder not only characterized by the presence of epidermal nevi but also by abnormalities in the internal organ systems. A small number of cases with KENS are molecularly characterized and reported in the literature with somatic activating RAS, FGFR3 and PIK3CA mutations.
Case presentation
In this study we present a patient with hyper- and hypopigmented regions, verrucous pigmented skin lesions and a paravertebral conglomerate tumour at the level of the cervical and thoracic spine. A large lipomatous dumbbell tumour caused atrophy of the spinal cord with progressive paraparesis. We identified a mosaic c.35G > A (p.Gly12Asp) KRAS mutation in the pigmented verrucous epidermal nevus tissue, the intraneural schwann cells and the lipoma. The c.35G > A (p.Gly12Asp) KRAS mutation was absent in the peripheral blood leukocytes.
We conclude that KENS, the intraneural Schwann cell proliferation and the lipoma in this individual were caused by a postzygotic and mosaic activating c.35G > A (p.Gly12Asp) KRAS mutation.
PMCID: PMC4422428  PMID: 25928347
Keratinocytic epidermal nevus syndrome; KRAS; Mosaicism; RASopathy; Somatic mutation
16.  Search for copy number variants in chromosomes 15q11-q13 and 22q11.2 in obsessive compulsive disorder 
BMC Medical Genetics  2010;11:100.
Obsessive-compulsive disorder (OCD) is a clinically and etiologically heterogeneous syndrome. The high frequency of obsessive-compulsive symptoms reported in subjects with the 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome) or Prader-Willi syndrome (15q11-13 deletion of the paternally derived chromosome), suggests that gene dosage effects in these chromosomal regions could increase risk for OCD. Therefore, the aim of this study was to search for microrearrangements in these two regions in OCD patients.
We screened the 15q11-13 and 22q11.2 chromosomal regions for genomic imbalances in 236 patients with OCD using multiplex ligation-dependent probe amplification (MLPA).
No deletions or duplications involving 15q11-13 or 22q11.2 were identified in our patients.
Our results suggest that deletions/duplications of chromosomes 15q11-13 and 22q11.2 are rare in OCD. Despite the negative findings in these two regions, the search for copy number variants in OCD using genome-wide array-based methods is a highly promising approach to identify genes of etiologic importance in the development of OCD.
PMCID: PMC2909937  PMID: 20565924
17.  Synpolydactyly and HOXD13 polyalanine repeat: addition of 2 alanine residues is without clinical consequences 
BMC Medical Genetics  2007;8:78.
Type II syndactyly or synpolydactyly (SPD) is clinically very heterogeneous, and genetically three distinct SPD conditions are known and have been designated as SPD1, SPD2 and SPD3, respectively. SPD1 type is associated with expansion mutations in HOXD13, resulting in an addition of ≥ 7 alanine residues to the polyalanine repeat. It has been suggested that expansions ≤ 6 alanine residues go without medical attention, as no such expansion has ever been reported with the SPD1 phenotype.
We describe a large Pakistani and an Indian family with SPD. We perform detailed clinical and molecular analyses to identify the genetic basis of this malformation.
We have identified four distinct clinical categories for the SPD1 phenotype observed in the affected subjects in both families. Next, we show that a milder foot phenotype, previously described as a separate entity, is in fact a part of the SPD1 phenotypic spectrum. Then, we demonstrate that the phenotype in both families segregates with an identical expansion mutation of 21 bp in HOXD13. Finally, we show that the HOXD13 polyalanine repeat is polymorphic, and the expansion of 2 alanine residues, evident in unaffected subjects of both families, is without clinical consequences.
It is the first molecular evidence supporting the hypothesis that expansion of ≤ 6 alanine residues in the HOXD13 polyalanine repeat is not associated with the SPD1 phenotype.
PMCID: PMC2222244  PMID: 18072967
18.  Ovarian dysfunction and FMR1 alleles in a large Italian family with POF and FRAXA disorders: case report 
BMC Medical Genetics  2007;8:18.
The association between premature ovarian failure (POF) and the FMR1 repeat number (41> CGGn< 200) has been widely investigated. Current findings suggest that the risk estimation for POF can be calculated in the offspring of women with pre-mutated FMR1 alleles.
Case presentation
We describe the coexistence in a large Italian kindred of Fragile X syndrome and familial POF in females with ovarian dysfunctions who carried normal or expanded FMR1 alleles. Genetic analysis of the FMR1 gene in over three generations of females revealed that six carried pre-mutated alleles (61–200), of which two were also affected by POF. However a young woman, who presented a severe ovarian failure with early onset, carried normal FMR1 alleles (<40). The coexistence within the same family of two dysfunctional ovarian conditions, one FMR1-related and one not FMR1-related, suggests that the complexity of familial POF conditions is larger than expected.
Our case study represents a helpful observation and will provide familial cases with heterogeneous etiology that could be further studied when candidate genes in addition to the FMR1 premutation will be available.
PMCID: PMC1859987  PMID: 17428316
19.  Coarctation of the aorta and mild to moderate developmental delay in a child with a de novo deletion of chromosome 15(q21.1q22.2) 
Deletion of 15q21q22 is a rare chromosomal anomaly. To date, there have been nine reports describing ten individuals with different segmental losses involving 15q21 and 15q22. Many of these individuals have common features of growth retardation, hypotonia and moderate to severe mental retardation. Congenital heart disease has been described in three individuals with interstitial deletion involving this region of chromosome 15.
Case presentation
We report a child with coarctation of the aorta, partial agenesis of corpus callosum and mild to moderate developmental delay, with a de novo deletion of 15q21.1q22.2, detected by the array Comparative Genomic Hybridization (CGH). We utilized chromosome 15-specific microarray-based CGH to define the chromosomal breakpoints in this patient.
This is the first description of mapping of an interstitial deletion involving the chromosome 15q21q22 segment using the chromosome 15-specific array-CGH. The report also expands the spectrum of clinical phenotype associated with 15q21q22 deletion.
PMCID: PMC1397801  PMID: 16472378
20.  Cryptic FMR1 mosaic deletion in a phenotypically normal mother of a boy with fragile X syndrome: case report 
BMC Medical Genetics  2014;15:125.
Increasing number of case reports of mosaic mutations and deletions have better armed clinicians and geneticists with more accurate and focused prenatal diagnoses. Since mosaicism means a significant increase of recurrence risk, detailed parental profiling is essential for risk assessments.
Case presentation
We here describe a clinically unaffected mother with a son who had fragile X syndrome (FXS) caused by a large deletion that includes the entire FMR1. To assess the recurrence risk regarding her second pregnancy, a series of genetic tests were conducted to establish this mother’s status. Routine single nucleotide polymorphism (SNP) array and fluorescence in situ hybridisation (FISH) analyses detected two normal FMR1 copies in her blood. However, in-depth studies across the deleted region revealed varying proportions of mosaic deletion in her somatic tissues: lowest in the blood, moderately higher in the skin, urine sediment and menstrual discharge and highest in her eyebrow. Further FISH analysis of her skin-derived fibroblasts confirmed mosaicism of 13%.
To our knowledge, this is the first characterized case of a female who was mosaic for an FMR1 deletion and extensive investigation of her mosaic status provided valuable information for her reproduction choices. Our case report may also alert clinicians and geneticists that a cryptic mosaicism with somatic heterogeneity should be carefully considered in families with children having clinically defined ‘de novo’ mutations, to avoid a second pregnancy with identical genetic abnormalities.
PMCID: PMC4411709  PMID: 25421229
Deletion; Fragile X syndrome; Mosaic; Somatic heterogeneity
21.  Familial imbalance in 16p13.11 leads to a dosage compensation rearrangement in an unaffected carrier 
BMC Medical Genetics  2014;15:116.
We and others have previously reported that familial cytogenetic studies in apparently de novo genomic imbalances may reveal complex or uncommon inheritance mechanisms.
A familial, combined genomic and cytogenetic approach was systematically applied to the parents of all patients with unbalanced genome copy number changes.
Discordant array-CGH and FISH results in the mother of a child with a prenatally detected 16p13.11 interstitial microduplication disclosed a balanced uncommon rearrangement in this chromosomal region. Further dosage and haplotype familial studies revealed that both the maternal grandfather and uncle had also the same 16p duplication as the proband. Genomic compensation observed in the mother probably occurred as a consequence of interchromosomal postzygotic nonallelic homologous recombination.
We emphasize that such a dualistic strategy is essential for the full characterization of genomic rearrangements as well as for appropriate genetic counseling.
PMCID: PMC4412105  PMID: 25358766
16p13.11 duplication; Gene dosage compensation; Homologous balanced rearrangement; Mitotic NAHR
22.  De novo deletion of chromosome 11q12.3 in monozygotic twins affected by Poland Syndrome 
BMC Medical Genetics  2014;15:63.
Poland Syndrome (PS) is a rare disorder characterized by hypoplasia/aplasia of the pectoralis major muscle, variably associated with thoracic and upper limb anomalies. Familial recurrence has been reported indicating that PS could have a genetic basis, though the genetic mechanisms underlying PS development are still unknown.
Case presentation
Here we describe a couple of monozygotic (MZ) twin girls, both presenting with Poland Syndrome. They carry a de novo heterozygous 126 Kbp deletion at chromosome 11q12.3 involving 5 genes, four of which, namely HRASLS5, RARRES3, HRASLS2, and PLA2G16, encode proteins that regulate cellular growth, differentiation, and apoptosis, mainly through Ras-mediated signaling pathways.
Phenotype concordance between the monozygotic twin probands provides evidence supporting the genetic control of PS. As genes controlling cell growth and differentiation may be related to morphological defects originating during development, we postulate that the observed chromosome deletion could be causative of the phenotype observed in the twin girls and the deleted genes could play a role in PS development.
PMCID: PMC4051386  PMID: 24885342
Chromosome 11q deletion; Congenital abnormalities; Monozygotic twins; Poland syndrome; CNV; HRASLS5; HRASLS2; RARRES3; PLA2G16
23.  EDAR-induced hypohidrotic ectodermal dysplasia: a clinical study on signs and symptoms in individuals with a heterozygous c.1072C > T mutation 
BMC Medical Genetics  2014;15:57.
Mutations in the EDAR-gene cause hypohidrotic ectodermal dysplasia, however, the oral phenotype has been described in a limited number of cases. The aim of the present study was to clinically describe individuals with the c.1072C > T mutation (p. Arg358X) in the EDAR gene with respect to dental signs and saliva secretion, symptoms from other ectodermal structures and to assess orofacial function.
Individuals in three families living in Sweden, where some members had a known c.1072C > T mutation in the EDAR gene with an autosomal dominant inheritance (AD), were included in a clinical investigation on oral signs and symptoms and self-reported symptoms from other ectodermal structures (n = 37). Confirmation of the c.1072C > T mutation in the EDAR gene were performed by genomic sequencing. Orofacial function was evaluated with NOT-S.
The mutation was identified in 17 of 37 family members. The mean number of missing teeth due to agenesis was 10.3 ± 4.1, (range 4–17) in the mutation group and 0.1 ± 0.3, (range 0–1) in the non-mutation group (p < 0.01). All individuals with the mutation were missing the maxillary lateral incisors and one or more of the mandibular incisors; and 81.3% were missing all four. Stimulated saliva secretion was 0.9 ± 0.5 ml/min in the mutation group vs 1.7 ± 0.6 ml/min in the non-mutation group (p < 0.01). Reduced ability to sweat was reported by 82% in the mutation group and by 20% in the non-mutation group (p < 0.01). The mean NOT-S score was 3.0 ± 1.9 (range 0–6) in the mutation group and 1.5 ± 1.1 (range 0–5) in the non-mutation group (p < 0.01). Lisping was present in 56% of individuals in the mutation group.
Individuals with a c.1072C > T mutation in the EDAR-gene displayed a typical pattern of congenitally missing teeth in the frontal area with functional consequences. They therefore have a need for special attention in dental care, both with reference to tooth agenesis and low salivary secretion with an increased risk for caries. Sweating problems were the most frequently reported symptom from other ectodermal structures.
PMCID: PMC4036832  PMID: 24884697
Ectodermal dysplasia; EDAR; Oligodontia; Orofacial function; Saliva; Sweating; Tooth agenesis
24.  LEOPARD syndrome: clinical dilemmas in differential diagnosis of RASopathies 
BMC Medical Genetics  2014;15:44.
Diagnosis within RASopathies still represents a challenge. Nevertheless, many efforts have been made by clinicians to identify specific clinical features which might help in differentiating one disorder from another. Here, we describe a child initially diagnosed with Neurofibromatosis-Noonan syndrome. The follow-up of the proband, the clinical evaluation of his father together with a gene-by-gene testing approach led us to the proper diagnosis.
Case presentation
We report a 8-year-old male with multiple café-au-lait macules, several lentigines and dysmorphic features that suggest Noonan syndrome initially diagnosed with Neurofibromatosis-Noonan syndrome. However, after a few years of clinical and ophthalmological follow-up, the absence of typical features of Neurofibromatosis type 1 and the lack of NF1 mutation led us to reconsider the original diagnosis. A new examination of the patient and his similarly affected father, who was initially referred as healthy, led us to suspect LEOPARD syndrome, The diagnosis was then confirmed by the occurrence in both patients of a heterozygous mutation c.1403 C > T, p.(Thr468Met), of PTPN11. Subsequently, the proband was also found to have type-1 Arnold-Chiari malformation in association with syringomyelia.
Our experience suggests that differential clinical diagnosis among RASopathies remains ambiguous and raises doubts on the current diagnostic clinical criteria. In some cases, genetic tests represent the only conclusive proof for a correct diagnosis and, consequently, for establishing individual prognosis and providing adequate follow-up. Thus, molecular testing represents an essential tool in differential diagnosis of RASophaties. This view is further strengthened by the increasing accessibility of new sequencing techniques.
Finally, to our knowledge, the described case represents the third report of the occurrence of Arnold Chiari malformation and the second description of syringomyelia with LEOPARD syndrome.
PMCID: PMC4005403  PMID: 24767283
LEOPARD syndrome; Neurofibromatosis type 1; RASopathy; PTPN11
25.  Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening 
BMC Medical Genetics  2014;15:26.
With a complex and extremely high clinical and genetic heterogeneity, autism spectrum disorders (ASD) are better dissected if one takes into account specific endophenotypes. Comorbidity of ASD with epilepsy (or paroxysmal EEG) has long been described and seems to have strong genetic background. Macrocephaly also represents a well-known endophenotype in subgroups of ASD individuals, which suggests pathogenic mechanisms accelerating brain growth in early development and predisposing to the disorder. We attempted to estimate the association of gene variants with neurodevelopmental disorders in patients with autism-epilepsy phenotype (AEP) and cranial overgrowth, analyzing two genes previously reported to be associated with autism and macrocephaly.
We analyzed the coding sequences and exon-intron boundaries of GLIALCAM, encoding an IgG-like cell adhesion protein, in 81 individuals with Autism Spectrum Disorders, either with or without comorbid epilepsy, paroxysmal EEG and/or macrocephaly, and the PTEN gene in the subsample with macrocephaly.
Among 81 individuals with ASD, 31 had concurrent macrocephaly. Head circumference, moreover, was over the 99.7th percentile (“extreme” macrocephaly) in 6/31 (19%) patients. Whilst we detected in GLIALCAM several single nucleotide variants without clear pathogenic effects, we found a novel PTEN heterozygous frameshift mutation in one case with “extreme” macrocephaly, autism, intellectual disability and seizures.
We did not find a clear association between GLIALCAM mutations and AEP-macrocephaly comorbidity. The identification of a novel frameshift variant of PTEN in a patient with “extreme” macrocephaly, autism, intellectual disability and seizures, confirms this gene as a major candidate in the ASD-macrocephaly endophenotype. The concurrence of epilepsy in the same patient also suggests that PTEN, and the downstream signaling pathway, might deserve to be investigated in autism-epilepsy comorbidity. Working on clinical endophenotypes might be of help to address genetic studies and establish actual causative correlations in autism-epilepsy.
PMCID: PMC3941568  PMID: 24580998
Autism spectrum disorders; Autism-epilepsy phenotype; Macrocephaly; GLIALCAM; PTEN

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