The copy number variation (CNV) of 15q11.2, an emerging and common condition observed during prenatal counseling, is encompassed by four highly conserved and non-imprinted genes-TUBGCP5, CYFIP1, NIPA1, and NIPA2-which are reportedly related to developmental delays or general behavioral problems. We retrospectively analyzed 1337 samples from genetic amniocentesis for fetal CNV using microarray-based comparative genomic hybridization analysis between January 2014 and December 2019. 15q11.2 CNV showed a prevalence of 1.5% (21/1337). Separately, 0.7% was noted for 15q11.2 BP1-BP2 microdeletion and 0.8% for 15q11.2 microduplication. Compared to the normal array group, the 15q11.2 BP1-BP2 microdeletion group had more cases of neonatal intensive care unit transfer, an Apgar score of <7 at 1 min, and neonatal death. Additionally, the group was symptomatic with developmental delays and had more infantile deaths related to congenital heart disease (CHD). Our study makes a novel contribution to the literature by exploring the differences in the adverse perinatal outcomes and early life conditions between the 15q11.2 CNV and normal array groups. Parent-origin gender-based differences may help in the prognosis of the fetal phenotype; development levels should be followed up in the long term and echocardiography should be offered prenatally and postnatally for the prevention of a delayed diagnosis of CHD.

The 15q11.2 BP1-BP2 microdeletion (Burnside-Butler) syndrome is emerging as the most frequent pathogenic copy number variation (CNV) in humans associated with neurodevelopmental disorders with changes in brain morphology, behavior, and cognition. In this study, we explored functions and interactions of the four protein-coding genes in this region, namely NIPA1, NIPA2, CYFIP1, and TUBGCP5, and elucidate their role, in solo and in concert, in the causation of neurodevelopmental disorders. First, we investigated the STRING protein-protein interactions encompassing all four genes and ascertained their predicted Gene Ontology (GO) functions, such as biological processes involved in their interactions, pathways and molecular functions. These include magnesium ion transport molecular function, regulation of axonogenesis and axon extension, regulation and production of bone morphogenetic protein and regulation of cellular growth and development. We gathered a list of significantly associated cardinal maladies for each gene from searchable genomic disease websites, namely MalaCards.org: HGMD, OMIM, ClinVar, GTR, Orphanet, DISEASES, Novoseek, and GeneCards.org. Through tabulations of such disease data, we ascertained the cardinal disease association of each gene, as well as their expanded putative disease associations. This enabled further tabulation of disease data to ascertain the role of each gene in the top ten overlapping significant neurodevelopmental disorders among the disease association data sets: (1) Prader-Willi Syndrome (PWS); (2) Angelman Syndrome (AS); (3) 15q11.2 Deletion Syndrome with Attention Deficit Hyperactive Disorder & Learning Disability; (4) Autism Spectrum Disorder (ASD); (5) Schizophrenia; (6) Epilepsy; (7) Down Syndrome; (8) Microcephaly; (9) Developmental Disorder, and (10) Peripheral Nervous System Disease. The cardinal disease associations for each of the four contiguous 15q11.2 BP1-BP2 genes are NIPA1- Spastic Paraplegia 6; NIPA2-Angelman Syndrome and Prader-Willi Syndrome; CYFIP1-Fragile X Syndrome and Autism; TUBGCP5-Prader-Willi Syndrome. The four genes are individually associated with PWS, ASD, schizophrenia, epilepsy, and Down syndrome. Except for TUBGCP5, the other three genes are associated with AS. Unlike the other genes, TUBGCP5 is also not associated with attention deficit hyperactivity disorder and learning disability, developmental disorder, or peripheral nervous system disease. CYFIP1 was the only gene not associated with microcephaly but was the only gene associated with developmental disorders. Collectively, all four genes were associated with up to three-fourths of the ten overlapping neurodevelopmental disorders and are deleted in this most prevalent known pathogenic copy number variation now recognized among humans with these clinical findings.

Primary microcephalies (MCPH) are characterized by microcephaly (HC -2 SD at birth) in the absence of visceral malformations. To date, less than 20 genes have been associated with MCHP, several of which are involved in the formation and function of the centrosome. Here, we report a novel missense variant in the TUBGCP5 gene in a patient with primary microcephaly and mild developmental delay. The TUBCGP5 gene (tubulin gamma complex associated protein 5) is a paralog of TUBGCP4 and TUBGCP6, both of which are known MCPH associated genes, and like its\' paralogs, is involved in centrosome formation. Furthermore, the TUBGCP5 gene is located in the 15q11.2 BP1-BP2 microdeletion Burnside-Butler susceptibility locus that is part of the larger Prader-Willi/Angelman region. Common clinical features of the 15q11.2 BP1-BP2 microdeletion include general developmental and neurodevelopmental delay which may occasionally be accompanied by yet unexplained microcephaly. In our patient, the TUBGCP5:c.2180T > G, p.Phe727Cys missense variant was identified in compound heterozygous state with 15q11.2 BP1-BP2 microdeletion using whole exome sequencing, after the initial analyses of known MCPH genes failed to identify a conclusively causative variant. The identified variant is rare and highly conserved, as shown by population allele frequency data from ExAC and GnomAD, as well as comparisons with all other vertebrates. Based on this evidence we suggest that the identified TUBGCP5 variant in our patient may thus represent a novel cause of MCPH with mild developmental delay and may play a role in occurrence of microcephaly in 15q11.2 microdeletion carriers. Further studies are required to further clarify the causality and penetrance of TBGCP5 variants in primary microcephaly.

OBJECTIVE: We present recurrent 15q11.2 (BP1-BP2) microdeletion encompassing NIPA1, NIPA2, CYFIP1, and TUBGCP5 in a family with phenotypic variability in developmental, speech, and motor delay.
METHODS: A 32-year-old woman underwent amniocentesis at 17 weeks of gestation because of an abnormal maternal serum screening result of Down syndrome risk of 1/226. Her husband was 31 years old. She and her husband were phenotypically normal, and there was no family history of mental disorders and congenital malformations. Amniocentesis revealed a karyotype of 46,XX. Prenatal ultrasound findings were unremarkable. A 2492-g female baby was delivered at 37 weeks of gestation uneventfully. During the subsequent pregnancy, the same woman at the age of 35 years underwent amniocentesis at 18 weeks of gestation because of advanced maternal age, which revealed a karyotype of 46,XY. Prenatal ultrasound findings were unremarkable. A 2780-g male baby was delivered at 37 weeks of gestation uneventfully. About 3 years after the birth of this boy, array comparative genomic hybridization of the family revealed 15q11.2 microdeletion encompassing NIPA1, NIPA2, CYFIP1, and TUBGCP5 in the two siblings, who displayed developmental, speech, and motor delay, and in their phenotypically normal father.
CONCLUSIONS: Recurrent phenotypic abnormality in the family with normal karyotype at amniocentesis should include a differential diagnosis of familial pathogenic copy-number variations.

Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients. This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease). Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, \'de novo\' microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies.