First prenatally diagnosed case of 16p11.2p12.1 duplication

Bourthoumieu, Sylvie; Esclaire, Françoise; Terro, Faraj; Fiorenza, Maryse; Aubard, Véronique; Malan, Valérie; Romana, Serge; Yardin, Catherine

doi:10.1002/pd.1949

Cited by 3 publications

(4 citation statements)

References 15 publications

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“…A prenatal case was excluded as no sonographic anomalies were found before termination of the pregnancy. 25 Only developmental and/or psychomotor delay was present in all patients. In one patient and the twins, normal development was followed by a marked decline after the age of 2.…”

Section: Discussionmentioning

confidence: 98%

16p11.2–p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2

et al. 2012

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Chromosome 16 contains multiple copy number variations (CNVs) that predispose to genomic disorders. Here, we differentiate pathogenic duplications of 16p11.2-p12.2 from microscopically similar euchromatic variants of 16p11.2. Patient 1 was a girl of 18 with autism, moderate intellectual disability, behavioural difficulties, dysmorphic features and a 7.71-Mb (megabase pair) duplication (16:21 521 005-29 233 146). Patient 2 had a 7.81-Mb duplication (16:21 382 561-29 191 527), speech delay and obsessional behaviour as a boy and, as an adult, short stature, macrocephaly and mild dysmorphism. The duplications contain 65 coding genes of which Polo-like kinase 1 (PLK1) has the highest likelihood of being haploinsufficient and, by implication, a triplosensitive gene. An additional 1.11-Mb CNV of 10q11.21 in Patient 1 was a possible modifier containing the G-protein-regulated inducer of neurite growth 2 (GPRIN2) gene. In contrast, the euchromatic variants in Patients 3 and 4 were amplifications from a 945-kb region containing non-functional immunoglobulin heavy chain (IGHV), hect domain pseudogene (HERC2P4) and TP53-inducible target gene 3 (TP53TG3) loci in proximal 16p11.2 (16:31 953 353-32 898 635). Paralogous pyrosequencing gave a total copy number of 3-8 in controls and 8 to >10 in Patients 3 and 4. The 16p11.2-p12.2 duplication syndrome is a recurrent genomic disorder with a variable phenotype including developmental delay, dysmorphic features, mild to severe intellectual disability, autism, obsessive or stereotyped behaviour, short stature and anomalies of the hands and fingers. It is important to differentiate pathogenic 16p11.2-p12.2 duplications from harmless, microscopically similar euchromatic variants of proximal 16p11.2, especially at prenatal diagnosis.

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Section: Discussionmentioning

confidence: 98%

16p11.2–p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2

et al. 2012

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“…All five genes have been described in conditions that demonstrate disease resulting from haploinsufficiency or loss of function of the gene product, so it is unclear whether triplication of these genes contribute to our patients' phenotypes. Evidence for dosage-sensitive genes in the 16p11.2-12.2 region is supported by previous reports of duplications associated with phenotypes including developmental delay, dysmorphic features, intellectual disability, autism spectrum disorder, microcephaly, short stature, and tapered fingers [Finelli et al, 2004;Behjati et al, 2008;Bourthoumieu et al, 2008;Tabet et al, 2012;Barber et al, 2013].…”

Section: Discussionmentioning

confidence: 70%

“…Of these, the most common is the 550 kb microdeletion at 16p11.2 that is estimated to be present in 1% of patients with autism spectrum disorder (ASD) [Weiss et al, 2008]. Duplications involving 16p11.1p13.1 [Kirchhoff et al, 2005], 16p11.2p12.1 [Engelen et al, 2002;Bourthoumieu et al, 2008], 16p11.2p12.2 [Finelli et al, 2004;Pani et al, 2010;Tabet et al, 2012;Barber et al, 2013], 16p11.2p13.1 [Behjati et al, 2008], 16p12.1p12.2 [Ballif et al, 2007], and 16p12.2 [Marshall et al, 2008;Itsara et al, 2009] have also been reported in association with neurodevelopmental disorders, congenital anomalies, and dysmorphic features, suggesting that a number of dosage-sensitive genes reside in that region. There is a single report of triplication involving 16p12.1 in a patient with intellectual disability, dysmorphic facial features, short stature, and hypotonia [Ballif et al, 2007].…”

Section: Introductionmentioning

confidence: 99%

Triplication of 16p12.1p12.3 associated with developmental and growth delay and distinctive facial features

Nimmo

Guerin

Badilla‐Porras

et al. 2015

American J of Med Genetics Pt A

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The 16p12 region is particularly prone to genomic disorders due to the large number of low copy repeats [Martin et al., 2004; Nature 432:988-994]. We report two unrelated patients with de novo triplication of 16p12.1p12.3 who had developmental delay and similar facial features. Patient 1 is a 4-year-old male with a congenital heart anomaly, bilateral cryptorchidism, chronic constipation, and developmental delay. Patient 2 is a 12-year-old female with prenatally diagnosed hydronephrosis, hepatobiliary disease, failure to thrive, and developmental delay. Distinctive facial features common to both patients include short palpebral fissures, bulbous nose, thin upper vermillion border, apparently lowset ears, and large ear lobes. We compare the clinical manifestations of our patients with a previously reported patient with triplication of 16p12.2.

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“…15,16 A 16p11.2p12.2 duplication identified prenatally was also reported. 17 Thus, the phenotype of the 16p11.2p12 duplication is not well defined.…”

Section: Introductionmentioning

confidence: 99%

Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother

et al. 2012

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The pericentromeric region of chromosome 16p is rich in segmental duplications that predispose to rearrangements through non-allelic homologous recombination. Several recurrent copy number variations have been described recently in chromosome 16p. 16p11.2 rearrangements (29.5-30.1 Mb) are associated with autism, intellectual disability (ID) and other neurodevelopmental disorders. Another recognizable but less common microdeletion syndrome in 16p11.2p12.2 (21.4 to 28.5-30.1 Mb) has been described in six individuals with ID, whereas apparently reciprocal duplications, studied by standard cytogenetic and fluorescence in situ hybridization techniques, have been reported in three patients with autism spectrum disorders. Here, we report a multiplex family with three boys affected with autism, including two monozygotic twins carrying a de novo 16p11.2p12.2 duplication of 8.95 Mb) characterized by single-nucleotide polymorphism array, encompassing both the 16p11.2 and 16p11.2p12.2 regions. The twins exhibited autism, severe ID, and dysmorphic features, including a triangular face, deep-set eyes, large and prominent nasal bridge, and tall, slender build. The eldest brother presented with autism, mild ID, early-onset obesity and normal craniofacial features, and carried a smaller, overlapping 16p11.2 microdeletion of 847 kb (28.40-29.25 Mb), inherited from his apparently healthy father. Recurrent deletions in this region encompassing the SH2B1 gene were recently reported in early-onset obesity and in individuals with neurodevelopmental disorders associated with phenotypic variability. We discuss the clinical and genetic implications of two different 16p chromosomal rearrangements in this family, and suggest that the 16p11.2 deletion in the father predisposed to the formation of the duplication in his twin children.

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First prenatally diagnosed case of 16p11.2p12.1 duplication

Cited by 3 publications

References 15 publications

16p11.2–p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2

16p11.2–p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2

Triplication of 16p12.1p12.3 associated with developmental and growth delay and distinctive facial features

Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother

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