Variants in Candidate Genes for Phenotype Heterogeneity in Patients with the 22q11.2 Deletion Syndrome.

22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with a broad and heterogeneous phenotype, even though most of the deletions present similar sizes, involving ∼3 Mb of DNA. In a relatively large population of a Brazilian 22q11.2DS cohort (60 patients), we investigated genetic variants that could act as genetic modifiers and contribute to the phenotypic heterogeneity, using a targeted NGS (Next Generation Sequencing) with a specific Ion AmpliSeq panel to sequence nine candidate genes (CRKL, MAPK1, HIRA, TANGO2, PI4KA, HDAC1, ZDHHC8, ZFPM2, and JAM3), mapped in and outside the 22q11.2 hemizygous deleted region. In silico prediction was performed, and the whole-genome sequencing annotation analysis package (WGSA) was used to predict the possible pathogenic effect of single nucleotide variants (SNVs). For the in silico prediction of the indels, we used the genomic variants filtered by a deep learning model in NGS (GARFIELD-NGS). We identified six variants, 4 SNVs and 2 indels, in MAPK1, JAM3, and ZFPM2 genes with possibly synergistic deleterious effects in the context of the 22q11.2 deletion. Our results provide the opportunity for the discovery of the co-occurrence of genetic variants with 22q11.2 deletions, which may influence the patients´ phenotype.

X-linked congenital adrenal hypoplasia: Report of long clinical follow-up and description of a new complex variant in the NR0B1 gene.

Adrenal hypoplasia congenita, attributed to NR0B1 pathogenic variants, accounts for more than 50% of the incidence of primary adrenal insufficiency in children. Although more than 250 different deleterious variations have been described, no genotype-phenotype correlation has been defined to date. We report a case of an adopted boy who reported the onset of an adrenal crisis at 2 weeks of age, requiring replacement therapy with mineralocorticoids and glucocorticoids for 4 months. For 3 years, he did well without treatment. At almost 4 years of age, the disorder was restarted. A long follow-up showed the evolution of hypogonadotropic hypogonadism. Molecular studies on NR0B1 revealed a novel and deleterious deletion-insertion-inversion-deletion complex rearrangement sorted in the 5'-3' direction, which is described as follows: (1) deletion of the intergenic region (between TASL and NR0B1 genes) and 5' region, (2) insertion of a sequence containing 37 bp at the junction of the intergenic region of the TASL gene and a part of exon 1 of the NR0B1 gene, (3) inversion of a part of exon 1, (4) deletion of the final portion of exon 1 and exon 2 and beginning of the 3'UTR region, (5) maintenance of part of the intergenic sequence (between genes MAGEB1 and NR0B1, telomeric sense), (6) large posterior deletion, in the same sense. The path to molecular diagnosis was challenging and involved several molecular biology techniques. Evaluating the breakpoints in our patient, we assumed that it was a nonrecurrent rearrangement that had not yet been described. It may involve a repair mechanism known as nonhomologous end-joining (NHEJ), which joins two ends of DNA in an imprecise manner, generating an "information scar," represented herein by the 37 bp insertion. In addition, the local Xp21 chromosome architecture with sequences capable of modifying the DNA structure could impact the formation of complex rearrangements.

Low-pass whole genome sequencing as a cost-effective alternative to chromosomal microarray analysis for low- and middle-income countries.

Low-pass whole genome sequencing (LP-WGS) has been applied as alternative method to detect copy number variants (CNVs) in the clinical setting. Compared with chromosomal microarray analysis (CMA), the sequencing-based approach provides a similar resolution of CNV detection at a lower cost. In this study, we assessed the efficiency and reliability of LP-WGS as a more affordable alternative to CMA. A total of 1363 patients with unexplained neurodevelopmental delay/intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies were enrolled. Those patients were referred from 15 nonprofit organizations and university centers located in different states in Brazil. The analysis of LP-WGS at 1x coverage (>50kb) revealed a positive testing result in 22% of the cases (304/1363), in which 219 and 85 correspond to pathogenic/likely pathogenic (P/LP) CNVs and variants of uncertain significance (VUS), respectively. The 16% (219/1363) diagnostic yield observed in our cohort is comparable to the 15%-20% reported for CMA in the literature. The use of commercial software, as demonstrated in this study, simplifies the implementation of the test in clinical settings. Particularly for countries like Brazil, where the cost of CMA presents a substantial barrier to most of the population, LP-WGS emerges as a cost-effective alternative for investigating copy number changes in cytogenetics.

Overlapping Spectrum of Craniofacial Microsomia Phenotype in Cat-Eye Syndrome.

This study reports three patients with Cat-eye Syndrome (CES), two of which present a previous clinical diagnosis of Craniofacial microsomia (CFM). Chromosomal microarray analysis (CMA) revealed a tetrasomy of 1,7 Mb at the 22q11.2q11.21 region, which is the typical region triplicated in the CES, in all patients. The most frequent craniofacial features found in individuals with CFM and CES are preauricular tags and/or pits and mandibular hypoplasia. We reinforce that the candidate genes for CFM features, particularly ear malformation, preauricular tags/pits, and facial asymmetry, can be in the proximal region of the 22q11.2 region.

How are people with orofacial clefts attended in northwest region of São Paulo state, Brazil?

Characterization of specific birth defects is essential for conducting scientific investigations, care and therapeutic strategies. This article describes demographic, clinical and genetic aspects, risk factors and access to treatment of Brazilian patients with orofacial clefts registered in a specialized collaborative center of the Brazilian Database on Craniofacial Anomalies (BDCA). We interviewed 70 individuals with typical orofacial clefts using a standard instrument from the database and subjected them to genetic testing. The patients were grouped as syndromic and non-syndromic. The majority of individuals were of lower middle class, native ancestry and syndromic. There was a significant difference in the type of clefts regarding gender. There was no significant difference between bilateral and unilateral, between the side affected, right and left, or familial recurrence related to type of oral cleft. The risk factor familial recurrence was significantly higher among non-syndromic cases. Etiological factors were identified or suggested in 62.5% of the syndromic cases. There was a delay in diagnosis and in access to treatment in most cases. We concluded that gender, native ancestry and low family income represent risk factors. Furthermore, the distribution by cleft types and gender is similar to previous studies. The results can guide scientific investigations and care policies.

Biallelic frameshift variant in the TBC1D2B gene in two siblings with progressive gingival overgrowth, fibrous dysplasia of face, and mental deterioration.

Biallelic loss-of-function variants in the TBC1D2B gene were recently reported as a cause of a neurodevelopmental disorder with seizures and gingival overgrowth. Here, we report two male siblings with the similar clinical characteristics. They started with gingival overgrowth and bilateral growth of soft tissues in the malar region at 3 years of age, which evolved with significant maxillary hypertrophy and compression of the brainstem due to fibrous dysplasia of facial bones. After disease evolution, they presented with mental deterioration, limb tremors, and gait ataxia. One of them also presented with seizures. Whole exome sequencing revealed a novel biallelic frameshift variant [c.595del; p.(Val199Trpfs*22)] in the TBC1D2B gene in both patients, which was confirmed and found in heterozygous state in each of their parents. There are strong similarities in clinical characteristics, age of onset, and evolution between the patients described here and cases reported in the literature, including cherubism-like phenotype with progressive gingival overgrowth and seizures. This is the fourth family in the world in which a biallelic loss-of-function variant in the TBC1D2B gene is associated with this phenotype. These results support that loss of TBC1D2B is the cause of this rare condition.

A Novel Look at Dosage-Sensitive Sex Locus Xp21.2 in a Case of 46,XY Partial Gonadal Dysgenesis without NR0B1 Duplication.

A region of 160 kb at Xp21.2 has been defined as dosage-sensitive sex reversal (DSS) and includes the NR0B1 gene, considered to be the candidate gene involved in XY gonadal dysgenesis if overexpressed. We describe a girl with 46,XY partial gonadal dysgenesis carrying a 297 kb duplication at Xp21.2 upstream of NR0B1 initially detected by chromosomal microarray analysis. Fine mapping of the breakpoints by whole-genome sequencing showed a tandem duplication of TASL (CXorf21), GK and partially TAB3, upstream of NR0B1. This is the first description of an Xp21.2 duplication upstream of NR0B1 associated with 46,XY partial gonadal dysgenesis.

Increased runs of homozygosity in the autosomal genome of Brazilian individuals with neurodevelopmental delay/intellectual disability and/or multiple congenital anomalies investigated by chromosomal microarray analysis.

Runs of homozygosity (ROH) in the human genome may be clinically relevant. The aim of this study was to report the frequency of increased ROH of the autosomal genome in individuals with neurodevelopmental delay/intellectual disability and/or multiple congenital anomalies, and to compare these data with a control group. Data consisted of calls of homozygosity from 265 patients and 289 controls. In total, 7.2% (19/265) of the patients showed multiple ROH exceeding 1% of autosomal genome, compared to 1.4% (4/289) in the control group (p=0.0006). Homozygosity ranged from 1.38% to 22.12% among patients, and from 1.53 to 2.40% in the control group. In turn, 1.9% (5/265) of patients presented ROH ≥10Mb in a single chromosome, compared to 0.3% (1/289) of individuals from the control group (p=0.0801). By excluding cases with reported consanguineous parents (15/24), the frequency of increased ROH was 3.4% (9/250) among patients and 1.7% (5/289) in the control group, considering multiple ROH exceeding 1% of the autosome genome and ROH ≥10Mb in a single chromosome together, although not statistically significant (p=0.1873). These results reinforce the importance of investigating ROH, which with complementary diagnostic tests can improve the diagnostic yield for patients with such conditions.

Brazil's Craniofacial Project: Different approaches on orofacial clefts and 22q11.2 deletion syndrome.

This article reports the present situation of Brazilian health care in genetics for Orofacial Cleft (OFC) and 22q11.2 Deletions Syndrome (22q11.2 DS) based on research conducted by Brazil's Craniofacial Project (BCFP). Established in 2003, BCFP is a voluntary and cooperative network aiming to investigate the health care of people with these diseases and other craniofacial anomalies. The initiatives and research results are presented in four sections: (a) a comprehensive report of the Brazilian public health system in craniofacial genetics; (b) multicentric studies developed on OFC and 22q11.2 DS; (c) education strategies focused on addressing these conditions for both population and health-care professionals; and (d) the nosology through the Brazilian Database on Craniofacial Anomalies (BDCA). Since 2006, BDCA uses a standardized method with detailed clinical data collection, which allows for conducting studies on nosology, genotype-phenotype correlations, and natural history; data can also contribute to public policies. Currently, the BDCA stores data on 1,724 individuals, including 1,351 (78.36%) who were primarily admitted due to OFC and 373 (21.63%) with clinical suspicion of 22q11.2 DS. Chromosomal abnormalities/genomic imbalances were represented by 92/213 (43.19%) individuals with syndromic OFC, including 43 with 22q11.2 DS, which indicates the need for chromosomal microarray analysis in this group. The nosologic diversity reinforces that monitoring clinical is the best strategy for etiological investigation. BCFP's methodology has introduced the possibility of increasing scientific knowledge and genetic diagnosis of OFC and 22q11.2 DS to in turn improve health care and policies for this group of diseases.

Genomic imbalances in craniofacial microsomia.

The aim of this study was to perform 22q11.2 deletion screening and chromosomal microarray analysis (CMA) in individuals clinically diagnosed with craniofacial microsomia (CFM) and review previously published cases of CFM with genomic imbalances. It included 54 individuals who were evaluated by a clinical geneticist. Copy number variants (CNVs) in the 22q11.2 region were investigated by multiplex ligation-dependent probe amplification (MLPA) for all individuals. The CMA was performed only for individuals with additional major features. MLPA revealed pathogenic CNVs at the 22q11 region in 3/54 (5.6%) individuals. CMA revealed pathogenic CNVs in 4/17 (23.5%) individuals, including the three CNVs at the 22q11 region also detected by MLPA, and CNVs classified as variants of unknown significance (VOUS) in 4/17 (23.5%) individuals. Pathogenic alterations were found at the 2p12, 5p15, 13q13, and 22q11 regions. VOUS were found at 3q29, 5q22.2, 5q22.1, and 9p22 regions. All individuals with pathogenic alterations presented additional major features, including congenital heart disease (CHD). The literature review revealed pathogenic CNVs in 17/193 (8.8%) individuals and most of them also presented additional major features, such as CHD, renal anomalies, or developmental delay. In conclusion, CNVs should be investigated in patients with CFM and additional major features.

Recessive and Dominant De Novo ITPR1 Mutations Cause Gillespie Syndrome.

Gillespie syndrome (GS) is a rare variant form of aniridia characterized by non-progressive cerebellar ataxia, intellectual disability, and iris hypoplasia. Unlike the more common dominant and sporadic forms of aniridia, there has been no significant association with PAX6 mutations in individuals with GS and the mode of inheritance of the disease had long been regarded as uncertain. Using a combination of trio-based whole-exome sequencing and Sanger sequencing in five simplex GS-affected families, we found homozygous or compound heterozygous truncating mutations (c.4672C>T [p.Gln1558(∗)], c.2182C>T [p.Arg728(∗)], c.6366+3A>T [p.Gly2102Valfs5(∗)], and c.6664+5G>T [p.Ala2221Valfs23(∗)]) and de novo heterozygous mutations (c.7687_7689del [p.Lys2563del] and c.7659T>G [p.Phe2553Leu]) in the inositol 1,4,5-trisphosphate receptor type 1 gene (ITPR1). ITPR1 encodes one of the three members of the IP3-receptors family that form Ca(2+) release channels localized predominantly in membranes of endoplasmic reticulum Ca(2+) stores. The truncation mutants, which encompass the IP3-binding domain and varying lengths of the modulatory domain, did not form functional channels when produced in a heterologous cell system. Furthermore, ITPR1 p.Lys2563del mutant did not form IP3-induced Ca(2+) channels but exerted a negative effect when co-produced with wild-type ITPR1 channel activity. In total, these results demonstrate biallelic and monoallelic ITPR1 mutations as the underlying genetic defects for Gillespie syndrome, further extending the spectrum of ITPR1-related diseases.

A Rare Case of Concomitant Deletions in 15q11.2 and 19p13.3.

A female individual with concomitant deletions in 15q11.2 and 19p13.3 is reported. She presents facial dysmorphisms, motor delay, learning difficulties, and mild behavioral impairment. After chromosomal microarray analysis, the final karyotype was established as 46,XX.arr[GRCh37] 15q11.2 (22770421_23282798)×1,19p13.3(3793904_4816330)×1. The deletion in 15q11.2 is 507 kb in size involving 7 non-imprinted genes, 4 of which are registered in the OMIM database and are implicated in neuropsychiatric or neurodevelopmental disorders. The deletion in 19p13.3 is 1,022 kb in size and encompasses 47 genes, most of which do not have a well-known function. The genotype-phenotype correlation is discussed, and most of the features could be related to the 19p13.3 deletion, except for velopharyngeal insufficiency. Other genes encompassed in the deleted region, as well as unrecognized epistatic factors could also be involved. Nevertheless, the two-hit model related to the 15q11.2 deletion would be an important hypothesis to be considered.

A recognizable phenotype related to 19p13.12 microdeletion.

Submicroscopic deletions in chromosome 19 have been rarely reported. We reported a male patient presenting with neurodevelopmental delay and facial dysmorphisms with a de novo 19p13.11p13.12 deletion of approximately 1.4 Mb. To date, there are seven cases with deletions overlapping the 19p13.11-p13.12 region described in the literature. A region of 800 kb for branchial arch defects in the proximal region of 19p13.12, and another minimal critical region of 305 kb for hypertrichosis, synophrys, and protruding front teeth have been proposed previously. We suggest that the shortest region of overlap could be refined to an approximately 53 kb region shared within all patients, encompassing part of BRD4 and AKAP8L genes and the AKAP8 gene. Based on the genotype-phenotype correlation of the present case and cases with overlapping deletions described in the literature, it was possible to recognize a consistent phenotype characterized by microcephaly, ear abnormalities, rounded face, synophrys, arched or upwardly angulated eyebrows, short nose, anteverted nares, prominent cheeks, teeth abnormalities, and developmental delay.

Application of high-resolution array platform for genome-wide copy number variation analysis in patients with nonsyndromic cleft lip and palate.

BACKGROUND: Although more than 14 loci may be involved in the development of nonsyndromic cleft lip and palate (NSCLP), the etiology has not been fully elucidated due to genetic and environmental risk factor interactions. Despite advances in identifying genes associated with the NSCLP development using traditional genetic mapping strategies of candidate genes, genome-wide studies, and epidemiologic and linkage analysis, microarray techniques have become important complementary tools in the search for potential causative oral clefts genes in genetic studies. Microarray hybridization enables scanning of the whole genome and detecting copy number variants (CNVs). Although common benign CNVs are often smaller, with sizes smaller than 20 kb, here we reveal small exonic CNVs based on the importance of the encompassed genes in cleft lip and palate phenotype. METHODS: Microarray hybridization analysis was performed in 15 individuals with NSCLP. RESULTS: We identified 11 exonic CNVs affecting at least one exon of the candidate genes. Thirteen candidate genes (COL11A1-1p21; IRF6-1q32.3; MSX1-4p16.2; TERT-5p15.33; MIR4457-5p15.33; CLPTM1L-5p15.33; ESR1-6q25.1; GLI3-7p13; FGFR-8p11.23; TBX1-22q11.21; OFD-Xp22; PHF8-Xp11.22; and FLNA-Xq28) overlapped with the CNVs identified. CONCLUSIONS: Considering the importance to NSCLP, the microdeletions that encompass MSX1, microduplications over TERT, MIR4457, CLPTM1L, and microduplication of PHF8 have been identified as small CNVs related to sequence variants associated with oral clefts susceptibility. Our findings represent a preliminary study on the clinical significance of small CNVs and their relationship with genes implicated in NSCLP.

DLX4 is associated with orofacial clefting and abnormal jaw development.

Cleft lip and/or palate (CL/P) are common structural birth defects in humans. We used exome sequencing to study a patient with bilateral CL/P and identified a single nucleotide deletion in the patient and her similarly affected son­c.546_546delG, predicting p.Gln183Argfs*57 in the Distal-less 4 (DLX4) gene. The sequence variant was absent from databases, predicted to be deleterious and was verified by Sanger sequencing. In mammals, there are three Dlx homeobox clusters with closely located gene pairs (Dlx1/Dlx2, Dlx3/Dlx4, Dlx5/Dlx6). In situ hybridization showed that Dlx4 was expressed in the mesenchyme of the murine palatal shelves at E12.5, prior to palate closure. Wild-type human DLX4, but not mutant DLX4_c.546delG, could activate two murine Dlx conserved regulatory elements, implying that the mutation caused haploinsufficiency. We showed that reduced DLX4 expression after short interfering RNA treatment in a human cell line resulted in significant up-regulation of DLX3, DLX5 and DLX6, with reduced expression of DLX2 and significant up-regulation of BMP4, although the increased BMP4 expression was demonstrated only in HeLa cells. We used antisense morpholino oligonucleotides to target the orthologous Danio rerio gene, dlx4b, and found reduced cranial size and abnormal cartilaginous elements. We sequenced DLX4 in 155 patients with non-syndromic CL/P and CP, but observed no sequence variants. From the published literature, Dlx1/Dlx2 double homozygous null mice and Dlx5 homozygous null mice both have clefts of the secondary palate. This first finding of a DLX4 mutation in a family with CL/P establishes DLX4 as a potential cause of human clefts.

Ancestry Informative Marker Panel to Estimate Population Stratification Using Genome-wide Human Array.

Case-control studies are a powerful strategy to identify candidate genes in complex diseases. In admixed populations, association studies can be affected by population stratification, leading to spurious genetic associations. Ancestry informative markers (AIMs) can be used to minimise this effect. The aim of this work was to select a set of AIMs to estimate population stratification in a Brazilian case-control study performed using a genome-wide array. A total of 345 single nucleotide polymorphism (SNP) AIMs, selected from the Cytoscan HD array and based on previously reported panels, was used to discriminate between European, African, and Amerindian populations. These SNP-AIMs were used to infer ancestry in systemic lupus erythematosus (SLE) patients (n = 23) and in healthy subjects (n = 110). Moderate population substructure was observed between SLE and control groups (Fst = 0.0113). Although patients and controls have shown a major European genomic contribution, significant differences in the European (P = 6.47 × 10-5 ) and African (P = 1.14 × 10-3 ) ancestries were detected between the two groups. We performed a two-step validation of the 345 SNP-AIMs panel estimating the ancestral contributions using a panel of 12 AIMs and approximately 70K SNPs from the array. Evaluation of population substructure in case-control studies, avoiding spurious genetic associations, can be performed using our panel of 345 SNP-AIMs.

A boy with partial dup(18q)/del(18p) due to a maternal pericentric inversion: Genotype-phenotype correlation and risk of recombinant chromosomes based on systematic review of the literature.

We report a boy carrying a recombinant chromosome 18, with terminal deletion of 10.8 Mb from 18p11.32 to 18p11.21 and a terminal duplication of 22.8 Mb from 18q21.31 to 18q23, resulting from a maternal pericentric inversion of the chromosome 18. He presented with poor growth, developmental delay, facial dysmorphisms, surgically repaired left cleft lip and palate, a mild form of holoprosencephaly characterized by single central incisor and agenesis of the septum pellucidum, and body asymmetry. Based on the systematic review of the literature, we discuss genotype-phenotype correlation and the risk for the recombinants of pericentric inversions of chromosome 18. © 2016 Wiley Periodicals, Inc.

22q11.2 deletion syndrome in diverse populations.

22q11.2 deletion syndrome (22q11.2 DS) is the most common microdeletion syndrome and is underdiagnosed in diverse populations. This syndrome has a variable phenotype and affects multiple systems, making early recognition imperative. In this study, individuals from diverse populations with 22q11.2 DS were evaluated clinically and by facial analysis technology. Clinical information from 106 individuals and images from 101 were collected from individuals with 22q11.2 DS from 11 countries; average age was 11.7 and 47% were male. Individuals were grouped into categories of African descent (African), Asian, and Latin American. We found that the phenotype of 22q11.2 DS varied across population groups. Only two findings, congenital heart disease and learning problems, were found in greater than 50% of participants. When comparing the clinical features of 22q11.2 DS in each population, the proportion of individuals within each clinical category was statistically different except for learning problems and ear anomalies (P < 0.05). However, when Africans were removed from analysis, six additional clinical features were found to be independent of ethnicity (P ≥ 0.05). Using facial analysis technology, we compared 156 Caucasians, Africans, Asians, and Latin American individuals with 22q11.2 DS with 156 age and gender matched controls and found that sensitivity and specificity were greater than 96% for all populations. In summary, we present the varied findings from global populations with 22q11.2 DS and demonstrate how facial analysis technology can assist clinicians in making accurate 22q11.2 DS diagnoses. This work will assist in earlier detection and in increasing recognition of 22q11.2 DS throughout the world.

Genotype-phenotype correlation of 16p13.3 terminal duplication and 22q13.33 deletion: Natural history of a patient and review of the literature.

This article reports a patient with a de novo ∼ 9.32 Mb duplication at 16p13.3 and a ∼ 71 Kb deletion at 22q13.33. The patient was followed from 1 month old to 3 years and 8 months of age and presented typical features of the 16p13.3 duplication syndrome. In addition, the patient presents a portal cavernoma, an alteration rarely reported in this condition. Renal agenesis was detected as additional developmental defect. After genomic array and FISH analysis, the karyotype was 46,XX,ins(22;16)(q13;p13.2p13.3). ish ins(22;16)(RP11-35P16+, RP11-27M24+). arr16p13.2p13.3(85,880-9,413,353)×3 dn arr22q13.33 (51,140,789-51,197,838)×1 dn. The authors provide a comprehensive review of the literature. This approach shed light on the genotype-phenotype correlation.

Tetrasomy 3q26.32-q29 due to a supernumerary marker chromosome in a child with pigmentary mosaicism of Ito.

Pigmentary mosaicism of Ito (PMI) is a skin abnormality often characterized by hypopigmentation of skin, following, in most cases, the Blaschko lines, usually associated with extracutaneous abnormalities, especially abnormalities of the central nervous system (CNS). It is suggested that this pattern arises from the presence and migration of two cell lineages in the ectoderm layer during the embryonic period and embryonic cell migration, with different gene expression profiles associated with pigmentation. Several types of chromosomal aberrations, with or without mosaicism, have been associated with this disorder. This study comprised clinical description and cytogenetic analysis of a child with PMI. The G-banded karyotype analysis revealed a supernumerary marker chromosome in 76% of the analyzed metaphases from peripheral blood lymphocytes. Array genomic hybridization analysis showed a copy number gain between 3q26.32-3q29, of approximately 20.5 Mb. Karyotype was defined as 47,XX,+mar[38]/46,XX[12].arr 3q26.32-3q29(177,682,859- 198,043,720)x4 dn. Genes mapped in the overlapping region among this patient and three other cases described prior to this study were listed and their possible involvement on PMI pathogenesis is discussed.