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Taiwan J Obstet Gynecol ; 60(4): 771-774, 2021 Jul.
Article En | MEDLINE | ID: mdl-34247823

OBJECTIVE: We present prenatal diagnosis of recurrent mosaic ring chromosome 13 [r(13)] of maternal origin. CASE REPORT: A 27-year-old woman underwent amniocentesis at 17 weeks of gestation because of a past history of fetal abnormality caused by mosaic r(13) in the previous fetus associated with fetal intrauterine growth restriction (IUGR), a karyotype of 46,XY,r(13)[23]/45,XY,-13[10]/46,XY,idic r(13)[2] and a maternal origin of abnormal r(13). The parental karyotypes were normal. During this pregnancy, amniocentesis revealed a karyotype of 46,XX,r(13)[12]/45,XX,-13[8] and a 22.80-Mb deletion of chromosome 13q31.3-q34. The pregnancy was subsequently terminated, and a malformed fetus was delivered with craniofacial dysmorphism. Repeat amniocentesis revealed a karyotype of 46,XX,r(13)(p11.1q31)[18]/45,XX,-13[12]. The placenta had a karyotype of 46,XX,r(13)(p11.1q31)[27]/45,XY,-13[13]. Polymorphic DNA marker analysis using the DNA derived from the parental bloods and umbilical cord confirmed a maternal origin of the abnormal r(13). CONCLUSION: Prenatal diagnosis of mosaic r(13) in consecutive pregnancies should raise a suspicion of parental gonadal mosaicism, and polymorphic DNA marker analysis is useful for determination of the parental origin of recurrent aneuploidy under such a circumstance.

Abnormalities, Multiple/diagnosis , Amniocentesis , Chromosome Disorders/diagnosis , Craniofacial Abnormalities/diagnosis , Abnormalities, Multiple/embryology , Abortion, Eugenic , Adult , Chromosome Deletion , Chromosome Disorders/embryology , Chromosomes, Human, Pair 13/genetics , Craniofacial Abnormalities/embryology , Female , Humans , Karyotype , Mosaicism/embryology , Pregnancy , Ring Chromosomes
Taiwan J Obstet Gynecol ; 60(4): 775-777, 2021 Jul.
Article En | MEDLINE | ID: mdl-34247824

OBJECTIVE: We present partial monosomy 8p (8p23.2→pter) and partial trisomy 15q (15q21.2→qter) and incidental detection of a familial chromosome translocation of paternal origin in a pregnancy associated with increased nuchal translucency (NT) and an abnormal maternal serum screening result. CASE REPORT: A 29-year-old primigravid woman underwent chorionic villus sampling (CVS) at 13 weeks of gestation because of an increased NT thickness of 3.2 mm at 12 weeks of gestation and an abnormal maternal serum screening for Down syndrome result with a calculated risk of 1/29. Her husband was 33 years old, and there was no family history of congenital malformations. CVS revealed a derived chromosome 8 or der(8). Cytogenetic analysis of the parents revealed a karyotype of 46,XY,t(8;15)(p21.3;q13) in the father and a karyotype of 46,XX in the mother. The CVS result was 46,XY,der(8)t(8;15)(p21.3;q13)pat. The woman requested for amniocentesis at 16 weeks of gestation. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed a result of arr 8p23.3p23.2 (191,530-2,625,470) × 1.0, arr 15q21.2q26.3 (50,903,432-102,338,129) × 3.0 with a 2.434-Mb deletion of 8p23.3-p23.2 including DLGAP2, CLN8 and ARHGEF10, and a 51.435-Mb duplication of 15q21.2-q26.3 including CYP19A1 and IGF1R. Conventional cytogenetic analysis of cultured amniocytes revealed the result of 46,XY,der(8) t(8;15)(p23.2;q21.2)pat in the fetus. The pregnancy was subsequently terminated, and a malformed fetus was delivered with characteristic craniofacial dysmorphism. CONCLUSION: Maternal serum screening and NT screening may incidentally detect familial unbalanced reciprocal translocations, and aCGH analysis is useful for a precise determination of the breakpoints of the translocation and the involvement of the related genes under such a circumstance.

Abnormalities, Multiple/diagnosis , Translocation, Genetic/genetics , Trisomy/diagnosis , Abnormalities, Multiple/embryology , Abnormalities, Multiple/genetics , Abortion, Eugenic , Adult , Chorionic Villi Sampling , Chromosome Deletion , Chromosomes, Human, Pair 15/genetics , Chromosomes, Human, Pair 8/genetics , Comparative Genomic Hybridization , Cytogenetic Analysis , Female , Humans , Incidental Findings , Male , Maternal Serum Screening Tests , Nuchal Translucency Measurement , Paternal Inheritance/genetics , Pregnancy , Trisomy/genetics
Sci Rep ; 11(1): 12861, 2021 06 18.
Article En | MEDLINE | ID: mdl-34145321

DCBLD2 encodes discodin, CUB and LCCL domain-containing protein 2, a type-I transmembrane receptor that is involved in intracellular receptor signalling pathways and the regulation of cell growth. In this report, we describe a 5-year-old female who presented severe clinical features, including restrictive cardiomyopathy, developmental delay, spasticity and dysmorphic features. Trio-whole-exome sequencing and segregation analysis were performed to identify the genetic cause of the disease within the family. A novel homozygous nonsense variant in the DCBLD2 gene (c.80G > A, p.W27*) was identified as the most likely cause of the patient's phenotype. This nonsense variant falls in the extracellular N-terminus of DCBLD2 and thus might affect proper protein function of the transmembrane receptor. A number of in vitro investigations were performed on the proband's skin fibroblasts compared to normal fibroblasts, which allowed a comprehensive assessment resulting in the functional characterization of the identified DCBLD2 nonsense variant in different cellular processes. Our data propose a significant association between the identified variant and the observed reduction in cell proliferation, cell cycle progression, intracellular ROS, and Ca2 + levels, which would likely explain the phenotypic presentation of the patient as associated with lethal restrictive cardiomyopathy.

Abnormalities, Multiple/genetics , Cardiomyopathy, Restrictive/genetics , Codon, Nonsense , Developmental Disabilities/genetics , Genetic Predisposition to Disease , Homozygote , Membrane Proteins/genetics , Abnormalities, Multiple/diagnosis , Alleles , Calcium/metabolism , Cardiomyopathy, Restrictive/diagnosis , Cardiomyopathy, Restrictive/metabolism , Cell Cycle/genetics , Child, Preschool , Consanguinity , Developmental Disabilities/diagnosis , Developmental Disabilities/metabolism , Facies , Female , Genetic Association Studies/methods , Genome, Mitochondrial , Genomics/methods , Humans , Magnetic Resonance Angiography , Phenotype , Radiography, Thoracic , Reactive Oxygen Species/metabolism , Whole Exome Sequencing
Eur J Med Genet ; 64(7): 104246, 2021 Jul.
Article En | MEDLINE | ID: mdl-34020006

The Ritscher-Schinzel syndrome (RTSCS) is a rare condition with craniofacial, cardiac and fossa posterior abnormalities. RTSCS is subdivided into Ritscher-Schinzel syndrome 1 (RTSCS1) caused by pathogenic variants in coiled-coil domain-containing protein 22 (CCDC22), and Ritscher-Schinzel syndrome 2 (RTSCS2) caused by pathogenic variants in WASH complex subunit 5 (WASHC5). CCDC22 is inherited in an X-linked recessive manner while WASHC5 is inherited in an autosomal recessive manner. Only 17 individuals with a molecular diagnosis are reported. In the past, the diagnosis of RTSCS was solely based on the clinical findings, and minimal diagnostic criteria has been proposed for the syndrome: Cardiac malformations (other than isolated patent ductus arteriosis), fossa posterior malformations, and certain dysmorphic features. However, those criteria are not present in all patients. We aim to further delineate the spectrum of CDCC22 associated RTSCS and present a novel patient with epileptic encephalopathy due to a presumed disease causing CCDC22 missense variant inherited from a healthy mother and grandmother. An affected maternal uncle had passed away at the age of 12 months and was thus unavailable for genetic testing. The proband and the maternal uncle had the typical facial dysmorphism associated with RTSCS, and they closely resembled previously published RTSCS2 patients with a molecular diagnosis. This suggests that RTSCS1 and RTSCS2 patients have a similar facial gestalt. We also review the literature on RTSCS, we explore potential differences and similarities between CCDC22 and W ASHC5 associated RTSCS and discuss the minimal diagnostic criteria.

Abnormalities, Multiple/genetics , Craniofacial Abnormalities/genetics , Dandy-Walker Syndrome/genetics , Heart Septal Defects, Atrial/genetics , Phenotype , Proteins/genetics , Abnormalities, Multiple/diagnosis , Adolescent , Craniofacial Abnormalities/diagnosis , Dandy-Walker Syndrome/diagnosis , Diagnosis, Differential , Heart Septal Defects, Atrial/diagnosis , Humans , Male , Mutation, Missense
Taiwan J Obstet Gynecol ; 60(3): 530-533, 2021 May.
Article En | MEDLINE | ID: mdl-33966742

OBJECTIVE: We present a novel homozygous splice site mutation in the PIGN gene identified by whole exome sequencing and explored the genotype-phenotype correlation. CASE REPORT: A healthy 32-year-old woman underwent an ultrasound at 13 + 5 weeks of gestation. The ultrasound revealed multiple anomalies again including cystic hygroma, omphalocele and a ventricular septal defect. The pregnancy was subsequently terminated, and whole exome sequencing revealed a novel homozygous splice site mutation in the PIGN gene c.963 G > A (p.Gln321Gln). The same variant was also detected by pedigree-based Sanger sequencing in both parents as heterozygous, while they had normal karyotypes. CONCLUSION: Our case report enhances the phenotype-genotype correlation associated with homozygous loss of function mutations in the PIGN gene.

Abnormalities, Multiple/diagnosis , DNA, Recombinant/genetics , Loss of Function Mutation/genetics , Phosphotransferases/genetics , Ultrasonography, Prenatal , Abnormalities, Multiple/embryology , Abnormalities, Multiple/genetics , Abortion, Eugenic , Adult , Female , Genetic Association Studies , Homozygote , Humans , Pedigree , Pregnancy , Whole Exome Sequencing
Taiwan J Obstet Gynecol ; 60(3): 549-550, 2021 May.
Article En | MEDLINE | ID: mdl-33966746

OBJECTIVE: We present rapid diagnosis of trisomy 18 of maternal origin by quantitative fluorescent polymerase chain reaction (QF-PCR) analysis following tissue culture failure for conventional cytogenetic analysis in a fetus with holoprosencephaly (HPE), ventricular septal defect (VSD), arthrogryposis of bilateral wrists and aplasia of the thumbs. CASE REPORT: A 22-year-old, primigravid woman was referred for first-trimester ultrasound screening at 13 weeks of gestation, and the fetus was found to have HPE and VSD. The pregnancy was subsequently terminated at 14 weeks of gestation, and a malformed fetus was delivered with cebocephaly, arthrogryposis of bilateral wrists and aplasia of the thumbs. The umbilical cord and placental tissues were collected for genetic analysis. However, tissue culture failure for conventional cytogenetic analysis occurred because of contamination. QF-PCR analysis using the polymorphic DNA markers of D18S1369 (18q12.2) and D18S1361 (18q22.3) confirmed trisomy 18 of maternal origin. CONCLUSION: QF-PCR analysis is useful for rapid confirmation of trisomy 18 and the parental origin when tissue culture failure for conventional cytogenetic analysis occurs in pregnancy suspicious of fetal trisomy 18.

Arthrogryposis/diagnosis , Heart Septal Defects, Ventricular/diagnosis , Holoprosencephaly/diagnosis , Polymerase Chain Reaction/methods , Trisomy 18 Syndrome/diagnosis , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/embryology , Abnormalities, Multiple/genetics , Abortion, Eugenic , Adult , Arthrogryposis/embryology , Arthrogryposis/genetics , Cytogenetic Analysis , Female , Genetic Testing , Heart Septal Defects, Ventricular/embryology , Heart Septal Defects, Ventricular/genetics , Holoprosencephaly/embryology , Holoprosencephaly/genetics , Humans , Pregnancy , Thumb/abnormalities , Trisomy 18 Syndrome/embryology , Trisomy 18 Syndrome/genetics , Wrist/abnormalities
Article En | MEDLINE | ID: mdl-33904266

Total anomalous pulmonary venous return is an uncommon congenital anomaly of the pulmonary venous system.  Excision of the common wall between the atrial septum and the coronary sinus and closure with a single patch is a popularly used technique to repair cardiac total anomalous pulmonary venous return. We have used the same approach in our patient: Our tutorial shows a simple method to divert pulmonary venous return into the mitral valve without causing damage to the internodal pathways.  Marking the coronary sinus is highlighted because using that landmark to locate the atrioventricular node is no longer possible after the common wall is cut.

Cardiac Surgical Procedures/methods , Scimitar Syndrome/surgery , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/surgery , Echocardiography , Heart Septal Defects, Atrial/diagnosis , Heart Septal Defects, Ventricular/diagnosis , Heart Septal Defects, Ventricular/surgery , Humans , Infant , Male , Scimitar Syndrome/diagnostic imaging
Genes (Basel) ; 12(3)2021 03 06.
Article En | MEDLINE | ID: mdl-33800913

Whole genome sequencing (WGS) is a powerful tool for postnatal genetic diagnosis, but relevant clinical studies in the field of prenatal diagnosis are limited. The present study aimed to prospectively evaluate the utility of WGS compared with chromosomal microarray (CMA) and whole exome sequencing (WES) in the prenatal diagnosis of fetal structural anomalies. We performed trio WGS (≈40-fold) in parallel with CMA in 111 fetuses with structural or growth anomalies, and sequentially performed WES when CMA was negative (CMA plus WES). In comparison, WGS not only detected all pathogenic genetic variants in 22 diagnosed cases identified by CMA plus WES, yielding a diagnostic rate of 19.8% (22/110), but also provided additional and clinically significant information, including a case of balanced translocations and a case of intrauterine infection, which might not be detectable by CMA or WES. WGS also required less DNA (100 ng) as input and could provide a rapid turnaround time (TAT, 18 ± 6 days) compared with that (31 ± 8 days) of the CMA plus WES. Our results showed that WGS provided more comprehensive and precise genetic information with a rapid TAT and less DNA required than CMA plus WES, which enables it as an alternative prenatal diagnosis test for fetal structural anomalies.

Abnormalities, Multiple/diagnosis , Chromosomes, Human/genetics , Microarray Analysis/methods , Whole Exome Sequencing/methods , Whole Genome Sequencing/methods , Abnormalities, Multiple/genetics , Female , Gestational Age , Humans , Pregnancy , Pregnancy Trimester, First , Prenatal Diagnosis , Prospective Studies
Clin Dysmorphol ; 30(3): 125-129, 2021 Jul 01.
Article En | MEDLINE | ID: mdl-33859080

Chromosomal aberrations are an important cause of multiple malformation syndromes. Multiple ligation-dependent probe amplification (MLPA) a molecular cytogenetic technique has been suggested as a screening tool for the detection of chromosomal aberrations in resource-limited settings. MLPA can detect chromosomal microdeletions or duplications at approximately 40 chromosomal regions in a single experiment. Several MLPA kits are available to target the chromosomal regions of interest. In the present study, we aimed to detect the yield and utility of MLPA in a cohort of children with multiple malformations and developmental delay. MLPA was performed using kits P245, P070 and P036. The overall yield of MLPA in our cohort was 8%. The manuscript describes very rare and interesting cases of congenital anomalies, such as severe buphthalmos and biphalangeal fingers with a chromosomal etiology. The study demonstrates the usefulness of MLPA as screening technique for chromosomal aberrations in children with multiple malformation syndromes, especially for developing countries such as India.

Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Cytogenetic Analysis/methods , Child , Child, Preschool , Chromosome Aberrations , Developing Countries , Female , Humans , Infant , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Karyotyping , Male , Mass Screening/methods
J Mother Child ; 24(3): 32-36, 2021 Apr 30.
Article En | MEDLINE | ID: mdl-33930262

The Mediator complex subunit 13-like is a part of the large Mediator complex. Recently, a large number of patients were diagnosed with mutations in this gene, which makes it one of the most frequent causes of syndromic intellectual disability. In this work, we report a patient with a novel de novo likely pathogenic variant c.5941C>T, p.(Gln1981*) in the MED13L gene with severe intellectual disability and facial dysmorphism. Uncommon findings like lack of speech, strabismus and self-destructive behaviour present in our patient allowed us to further define the phenotypic spectrum of mental retardation and distinctive facial features with or without cardiac defects syndrome.

Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Abnormalities, Multiple/physiopathology , Haploinsufficiency , Intellectual Disability/genetics , Loss of Function Mutation , Mediator Complex/genetics , Child , Genetic Variation , Humans , Intellectual Disability/diagnosis , Intellectual Disability/physiopathology , Male , Mutation , Phenotype
Cardiol Young ; 31(11): 1850-1852, 2021 Nov.
Article En | MEDLINE | ID: mdl-33879276

DiGeorge syndrome is a rare spectrum of disorder affecting structures derived from third and fourth pharyngeal pouches characterised by aplasia or hypoplasia of thymus and parathyroid glands, and conotruncal anomalies. Presentation includes infants with hypocalcemic seizures, CHD, or recurrent infection. This case report illustrates a unique combination of proximal interruption of right pulmonary artery and aberrant right subclavian artery in a 3-month-old infant who was subsequently diagnosed as DiGeorge syndrome. This constellation of vascular anomalies in an infant with DiGeorge syndrome has not been previously reported in the literature.

Abnormalities, Multiple , DiGeorge Syndrome , Heart Defects, Congenital , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 22/genetics , DiGeorge Syndrome/complications , DiGeorge Syndrome/diagnosis , DiGeorge Syndrome/genetics , Humans , Infant , Pulmonary Artery/diagnostic imaging , Subclavian Artery/diagnostic imaging
BMJ Case Rep ; 14(3)2021 Mar 03.
Article En | MEDLINE | ID: mdl-33658211

A 2-month-old boy presented to us with bilateral microtia, left lower motor neuron facial palsy, micrognathia, hemivertebra, bifid rib, bifid thumb and absent/hypoplastic right-sided depressor anguli oris. He had bilateral external auditory canal atresia, although response to loud sound was present. Brain stem evoked response audiometry (BERA) was advised at 3 months of age. Karyotype was normal. We diagnosed him as a case of oculo-auriculo-vertebral spectrum. Child was discharged on request by the family with the plan for bone-anchored hearing aid after BERA and plan for pinna and ear canal reconstruction at a later age but child did not come for any follow-up visit. On telephonic enquiry, it was found that he is thriving well but has developmental delay including speech delay. We conclude that children presenting with external ear abnormalities should be screened for multiple congenital anomalies so that a multidisciplinary approach to management can be planned.

Abnormalities, Multiple , Hearing Aids , Abnormalities, Multiple/diagnosis , Child , Ear Canal , Family , Humans , Infant , Male , Spine
Am J Med Genet A ; 185(6): 1732-1742, 2021 06.
Article En | MEDLINE | ID: mdl-33683014

Prenatal testing has changed greatly over the past two decades, which may affect the diagnosis of congenital heart disease (CHD) in Down syndrome. The present study aimed to analyze changes in the prevalence and distribution of CHD diagnosed via ultrasonography and fetopathology in 462 fetuses with trisomy 21 between two consecutive 10-year periods (1999-2018), as well as the associations between CHDs, ultrasound markers, and extracardiac malformations. Overall, the frequency of cardiovascular malformations in trisomy 21 was 27.7 and 26.5%, and ultrasound identified 70 and 62% of CHDs during these periods. A profound increase in first-trimester ultrasound findings and associated anomalies with CHDs (ventricular septal defect, Tetralogy of Fallot) since 2009 were observed. Second-trimester nonstructural heart abnormalities were associated with ultrasound anomalies (74%) and major extracardiac malformations (42.9%). During both study periods, mothers carrying fetuses with CHD were significantly younger than those without CHD (p = 0.038, p = 0.009, respectively). Comparing the two 10-year periods, there were no changes in the prevalence and detection of CHDs. Trend analysis revealed that, although the frequency of CHD remained stable, the diagnostic spectrum had shifted between the study periods. Detection of nonstructural heart abnormalities necessitates detailed follow-up for cardiac/extracardiac malformations and chromosomal disorders.

Abnormalities, Multiple/diagnosis , Down Syndrome/diagnosis , Heart Defects, Congenital/diagnosis , Prenatal Diagnosis , Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/epidemiology , Adult , Chromosome Aberrations , Down Syndrome/complications , Down Syndrome/diagnostic imaging , Down Syndrome/epidemiology , Female , Heart Defects, Congenital/complications , Heart Defects, Congenital/diagnostic imaging , Heart Defects, Congenital/epidemiology , Humans , Male , Maternal Age , Pregnancy , Pregnancy Trimester, First , Pregnancy Trimester, Second , Ultrasonography, Prenatal/methods , Young Adult
J Obstet Gynaecol Res ; 47(6): 2242-2245, 2021 Jun.
Article En | MEDLINE | ID: mdl-33723897

Herlyn-Werner-Wunderlich (HWW) syndrome is a rare congenital anomaly of Mullerian duct development characterized by uterus didelphys with blind hemivagina and ipsilateral renal agenesis. We present a case of a 29-year-old nulliparous woman, who was referred to our hospital complaining of chronic pelvic pain, dyspareunia, and a palpable mass in her vagina. At the age of 12, she underwent surgery because of a didelphys uterus diagnosis. Subsequently, she was operated on twice for endometriomas. At our institution, clinical and imaging findings revealed an obstructed hemivagina setting the diagnosis of HWW syndrome. Some of the various syndrome types may go unnoticed for months or even years after the onset of menstruation. Early diagnosis, followed by proper surgical treatment, is the key to avoid potentially severe complications.

Abnormalities, Multiple , Kidney Diseases , Urogenital Abnormalities , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/surgery , Adult , Female , Humans , Kidney/diagnostic imaging , Kidney/surgery , Uterus/diagnostic imaging , Uterus/surgery , Vagina/surgery
Am J Med Genet A ; 185(4): 1270-1274, 2021 04.
Article En | MEDLINE | ID: mdl-33547739

A 5-year-old girl presented with treatment-refractory dry eye and recurrent episodes of eye pain. She had been previously diagnosed with syndromic congenital sodium diarrhea (SCSD) caused by a pathogenic variant in SPINT2. Her local pediatric ophthalmologist had made the diagnosis of severe dry eye with corneal erosions, based on which, we arranged an eye exam under anesthesia (EUA) and punctal plug placement. Anterior segment optical coherence tomography (OCT) and corneal photographs were taken during the procedure. There are reports describing similar ophthalmic findings in this syndrome. However, to the best of our knowledge, this is the first case report to document OCT imaging and corneal photographs in a patient with SCSD, which we feel expands the ophthalmic phenotype of this rare genetic disorder.

Abnormalities, Multiple/genetics , Diarrhea/congenital , Membrane Glycoproteins/genetics , Metabolism, Inborn Errors/genetics , Sodium/metabolism , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/pathology , Child, Preschool , Cornea/metabolism , Cornea/pathology , Diarrhea/diagnosis , Diarrhea/diagnostic imaging , Diarrhea/genetics , Diarrhea/pathology , Humans , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/diagnostic imaging , Metabolism, Inborn Errors/pathology , Mutation/genetics , Phenotype , Tomography, Optical Coherence/methods
Am J Med Genet A ; 185(4): 1261-1265, 2021 04.
Article En | MEDLINE | ID: mdl-33577136

Haploinsufficiency of AUTS2 has been associated with neurodevelopmental disorders and dysmorphic features (MIM # 615834). More than 50 patients have been described, mostly carrying de novo deletions of one or more exons, including eight patients with exon 6 deletions. We report on two siblings, a girl and a boy aged 11 and 13 years, in whom the same pathogenic 85 kb deletion on 7q11.22 encompassing exon 6 of AUTS2 by SNP array analysis was identified. Both children had typical symptoms of AUTS2 syndrome such as intellectual impairment and behavioral problems, but with markedly different expression. SNP array analysis excluded the deletion in blood samples of both parents and a healthy brother. Conventional karyotyping of both parents and additional FISH analyses, marking the flanking regions of the deletion, did not show any structural rearrangements involving 7q11.22. A germ cell mosaicism was suggested as the most probable explanation for occurrence of the same deletion in these two siblings. To our knowledge this is the first report of germ cell mosaicism for AUTS2 syndrome. It additionally provides further evidence of intrafamilial phenotypic variability in AUTS2 syndrome and adds clinical information to the phenotypic spectrum of patients with AUTS2 exon 6 deletions.

Abnormalities, Multiple/genetics , Cytoskeletal Proteins/genetics , Developmental Disabilities/genetics , Intellectual Disability/genetics , Transcription Factors/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/pathology , Adolescent , Child , Developmental Disabilities/diagnosis , Developmental Disabilities/pathology , Exons/genetics , Female , Germ Cells/metabolism , Germ Cells/pathology , Haploinsufficiency/genetics , Humans , Intellectual Disability/diagnosis , Intellectual Disability/pathology , Male , Mosaicism , Sequence Deletion/genetics
Am J Med Genet A ; 185(5): 1379-1387, 2021 05.
Article En | MEDLINE | ID: mdl-33522143

Decades of clinical, pathological, and epidemiological study and the recent application of advanced microarray and gene sequencing technologies have led to an understanding of the causes and pathogenesis of most recognized patterns of malformation. Still, there remain a number of patterns of malformation whose pathogenesis has not been established. Six such patterns of malformation are sirenomelia, VACTERL association, OEIS complex, limb-body wall defect (LBWD), urorectal septum malformation (URSM) sequence, and MURCS association, all of which predominantly affect caudal structures. On the basis of the overlap of the component malformations, the co-occurrence in individual fetuses, and the findings on fetal examination, a common pathogenesis is proposed for these patterns of malformation. The presence of a single artery in the umbilical cord provides a visible clue to the pathogenesis of all cases of sirenomelia and 30%-50% of cases of VACTERL association, OEIS complex, URSM sequence, and LBWD. The single artery is formed by a coalescence of arteries that supply the yolk sac, arises from the descending aorta high in the abdominal cavity, and redirects blood flow from the developing caudal structures of the embryo to the placenta. This phenomenon during embryogenesis is termed vitelline vascular steal.

46, XX Disorders of Sex Development/diagnosis , Abnormalities, Multiple/diagnosis , Anal Canal/abnormalities , Congenital Abnormalities/diagnosis , Ectromelia/diagnosis , Esophagus/abnormalities , Heart Defects, Congenital/physiopathology , Kidney/abnormalities , Limb Deformities, Congenital/physiopathology , Mullerian Ducts/abnormalities , Spine/abnormalities , Trachea/abnormalities , 46, XX Disorders of Sex Development/physiopathology , Abnormalities, Multiple/physiopathology , Anal Canal/blood supply , Anal Canal/physiopathology , Anus, Imperforate/physiopathology , Aorta/pathology , Arteries/pathology , Congenital Abnormalities/physiopathology , Ectromelia/physiopathology , Embryo, Mammalian , Esophagus/blood supply , Esophagus/physiopathology , Extremities/blood supply , Extremities/embryology , Extremities/growth & development , Female , Fetus , Hernia, Umbilical/physiopathology , Humans , Kidney/blood supply , Kidney/physiopathology , Mullerian Ducts/blood supply , Mullerian Ducts/physiopathology , Pregnancy , Scoliosis/physiopathology , Spine/blood supply , Spine/physiopathology , Torso/blood supply , Torso/physiopathology , Trachea/blood supply , Trachea/physiopathology , Umbilical Cord/blood supply , Umbilical Cord/physiopathology , Urogenital Abnormalities/physiopathology