Terminal chromosome 4q deletion syndrome in an infant with hearing impairment and moderate syndromic features: review of literature

Abstract

BackgroundTerminal deletions of chromosome 4q are associated with a broad spectrum of phenotypes including cardiac, craniofacial, digital, and cognitive impairment. The rarity of this syndrome renders genotype-phenotype correlation difficult, which is further complicated by the widely different phenotypes observed in patients sharing similar deletion intervals.Case presentationHerein, we describe a boy with congenital hearing impairment and a variety of moderate syndromic features that prompted SNP array analysis disclosing a heterozygous 6.9 Mb deletion in the 4q35.1q35.2 region, which emerged de novo in the maternal germ line.ConclusionIn addition to the index patient, we review 35 cases from the literature and DECIPHER database to attempt genotype-phenotype correlations for a syndrome with great phenotypic variability. We delineate intervals with recurrent phenotypic overlap, particularly for cleft palate, congenital heart defect, intellectual disability, and autism spectrum disorder. Broad phenotypic presentation of the terminal 4q deletion syndrome is consistent with incomplete penetrance of the individual symptoms.

Molecular cytogenetic characterization of a 2q35‐q37 duplication and a 4q35.1‐q35.2 deletion in two cousins: A genotype–phenotype analysis

“…Our patients support this hypothesis, as neither one presents any sign of PRS [Rossi et al, ]. Finally, the 4q3 deletion has been recently associated to mild to severe bilateral hearing loss; the CASP3 gene, which is required for proper functioning of the cochlea, is the candidate gene [Vona et al, ]. However, a number of cases with 2q3 duplication also reported hearing impairment [Laurent et al, ; Yu and Chen, ; Richter et al, ; Dahoun‐Hadorn and Bretton‐Chappuis, ; Fritz et al, ; Angle et al, ; Bonaglia et al, ; Bird and Mascarello, ; Hermsen et al, ; Elbrach et al, ; Rashidi‐Nezhad et al, ].…”

“…One of the life‐threatening anomalies of 4q deletion syndrome is CHD [Strehle and Bantock, ]. It has been proposed that CHD could be associated with multiple 4q3 loci one within the 170–181 Mb interval containing two genes, TLL1 and HAND2 , involved in cardiac morphogenesis; the other more distal within the 4q35 band and containing two adiacent genes, PDLIM3 and SORBS2 , implicated in cardiac development [Maurin et al, ; Rashidi‐Nezhad et al, ; Vona et al, ]. Our patients, though heterozygous for the 4q35.1 band, are not affected by CHD, suggesting that haploinsufficiency of the candidate genes could have an incomplete penetrance.…”

“…Common clinical features include intellectual disability, a wide variety of head and facial abnormalities such as hypertelorism, malformed ears, cleft palate, short nose, congenital heart, and genitourinary defects [Maurin et al, ; Rashidi‐Nezhad et al, ; Strehle et al, ; Hemmat et al, ]. A number of cases of 4q deletion overlapping the 4q35.1‐q35.2 region have been reported: few of these have been isolated terminal 4q deletions, while the majority of patients also exhibited additional chromosomal rearrangements [Descartes et al, ; Tsai et al, ; Van Buggenhout et al, ; Cingoz et al, ; Vogt et al, ; Bendavid et al, ; Connel et al, ; Quadrelli et al, ; Bartholdi et al, ; Kaalund et al, ; Kitsiou‐Tzeli et al, ; Russel et al, ; Sensi et al, ; Maurin et al, ; Rossi et al, ; Chien et al, ; Markiewicz et al, ; Khalifa et al, ; Hemmat et al, ; Vona et al, ] (Fig. ).…”

“…However, a number of cases with 2q3 duplication also reported hearing impairment [Laurent et al, ; Yu and Chen, ; Richter et al, ; Dahoun‐Hadorn and Bretton‐Chappuis, ; Fritz et al, ; Angle et al, ; Bonaglia et al, ; Bird and Mascarello, ; Hermsen et al, ; Elbrach et al, ; Rashidi‐Nezhad et al, ]. Thus, a cumulative effect of rare, pathogenic variants in different deafness genes scattered across the genome could contribute to hearing impairment [Vona et al, ].…”

A familial interstitial 4q35 deletion with no discernible clinical effects

“…And also, they discussed disease relevant genes located in the deleted region in their case. Detailes of these reviews are available in the supplementary material of their report [Vona et al, ].…”