Molecular characterization of distal 4q duplication in two patients using oligonucleotide array‐based comparative genomic hybridization (oaCGH) analysis

Abstract

Pure/direct duplications on the long arm of chromosome 4 represent an infrequent chromosomal finding. Description of clinical findings in 30 patients has resulted in defining the 4q-associated phenotype. However, such duplications have not been molecularly or genomically characterized yet, limiting genotype-phenotype correlation. We report on the first two patients with a duplication involving the distal third of 4q that are characterized molecularly and genomically. Clinical features in our patients typical of 4q duplication syndrome included mild intellectual disability, cranial malformation, minor facial dysmorphism, and digital anomaly. Duplication of the segment 4q33-4q34, appears to be the critical region resulting in the phenotype associated with 4q duplication syndrome. The genes GLRA3, GMP6A that are invovled in neurogenesis and HAND2 in craniofacial development, within the duplicated region of 4q, may play a key role in the clinical phenotype. As more reporting on molecular characterization of 4q duplication becomes available, the role of these underlying genes may become clearer.

Complex Small Supernumerary Marker Chromosome Leading to Partial 4q/21q Duplications: Clinical Implication and Review of the Literature

“…HAND2 (OMIM 602407) encodes a basic helix-loop-helix transcription factor that is expressed in the heart. Despite the association of 4q deletion with cardiac defects, duplication of the HAND2 gene seems not to be associated with cardiac malformation, as observed in our patient and in 2 patients described by Thapa et al [2014].…”

“…Pure partial 4q duplication usually results in growth deficiency, developmental delay, intellectual disability, microcephaly, facial dysmorphism (broad/prominent nasal bridge, prominent/low-set ears, downslanting palpebral fissures, epicanthic folds, hypertelorism), and digital anomalies (clinodactyly of fifth finger, hypoplastic thumb) [Rinaldi et al, 2003;Lin et al, 2004]. To our knowledge, there is only 1 previous report of a patient with a pure 4q32.1q35.2 duplication [Thapa et al, 2014]. The male patient presented with mild intellectual disability, psychomotor/cognitive delay, craniosynostosis, mild dysmorphic features (high forehead, micrognathia, short philtrum, and broad nasal bridge), digital anomalies, and cryptorchidism.…”

“…There are a total of 234 RefSeq genes located in the 4q32.1q35.2 region, 74 of which are OMIM genes. The segment 4q33q34 harbors GLRA3 , GMP6A , and HAND2 , which are candidate genes for the common clinical manifestation of 4q duplication syndrome [Thapa et al, 2014]. The GLRA3 gene (OMIM 600421) encodes the α-3 subunit of the neuronal glycine receptor essential for synaptogenesis, and the GMP6A gene (OMIM 601275) encodes M6, which is a neuronal membrane glycoprotein that may have an important role in neural development.…”

Fetal Cerebral Ventricular Dilatation: Etiopathogenic Study of 130 Observations

“…The phenotype associated with chromosomal syndrome fit well the 6q microdeletion syndrome in our case. In fact, the partial distal trisomy 4q is involved in the psychomotor developmental delay, whereas the terminal 6q deletion is consistently associated with brain anomalies encompassing CVD, CC agenesis, PVNH, polymicrogyria, and cerebellar malformations (Thapa et al, ; Peddibhotla et al, ). Otherwise, the recurrence in siblings, identified in one family, raises the possibility of an autosomal recessive pattern of inheritance.…”

Duplicación parcial 4q en un neonato originado por reordenamiento der (20), t(4;20) (q21;q13.1)mat

“…En nuestra institución aún no se ha implementado pruebas que combinen la citogenética clásica con la biología molecular para comprobar la presencia o ausencia de los segmentos involucrados mediante el uso de sondas teloméricas con técnicas de hibridización in situ por determinar el origen de esta condición 12,14,16,19,20,22,23,25,26,44,50 . array o (Hibridación Genómica Comparativa) contribuyen a caracterizar de manera más precisa la extensión de la ganancia o pérdida de genes o regiones génicas en aquellos individuos que poseen el desbalance cromosómico ya sea de novo o heredado de portadores balanceados de translocaciones recíprocas 19,25,50,51 se adicional y sus efectos en el fenotipo de los individuos afectados. Estas técnicas a pesar que son una práctica rutinaria en otras sociedades aún no se han adoptado en nuestro medio.…”