A familial interstitial 4q35 deletion with no discernible clinical effects

Yakut, Sezin; Clarck, Ozden Altiok; Sanhal, Cem Yaşar; Nur, Banu; Mendilcioğlu, İnanç; Karaüzüm, Sibel Berker; Çetin, Zafer

doi:10.1002/ajmg.a.37097

Cited by 10 publications

(8 citation statements)

References 20 publications

(32 reference statements)

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“…Also, while their case had a heterozygous deletion of 4q35.2, they believe that the clinical manifestations of the case were due to the duplication of the chromosome 2q34 region. Strikingly, in the family described by Yakut et al [2015], no clinical effect was observed in either the mother or her 2 daughters, even though they each had a 5.75-Mb deletion in the chromosome 4q35.1q35.2 region. Based on the findings of these 2 publications and our case, it appears that the chromosome 4q35.2 region can be polymorphic.…”

Section: Discussionmentioning

confidence: 88%

Coexistence of a Homozygous Chromosome 4q35.2 Deletion and Hidden IQSEC2 Pathogenic Variant in a Child with Intellectual Disability

Mercan

Clark

Erkal

et al. 2021

Cytogenet Genome Res

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Terminal deletions in the long arm of chromosome 4 are an uncommon event, with a worldwide incidence of approximately 0.001%. The majority of these deletions occur de novo. Terminal deletion cases are usually accompanied by clinical findings that include facial and cardiac anomalies, as well as intellectual disability. In this study, we describe the case of a 2-year-old girl, the fourth child born to consanguineous parents. While her karyotype was normal, a homozygous deletion was identified in the chromosome 4q35.2 region by subtelomeric FISH. A heterozygous deletion of the chromosome 4q35.2 region was observed in both parents. According to the literature, this is the first report of a case that has inherited a homozygous deletion of chromosome 4qter from carrier parents. Subsequent array-CGH analyses were performed on both the case and her parents. Whole-exome sequencing was also carried out to determine potential variants. We detected a NM_001111125.3:c.2329G>T (p.Glu777Ter) nonsense variant of the IQSEC2 gene in the girl, a variant that is related to X-linked intellectual disability.

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Section: Discussionmentioning

confidence: 88%

Coexistence of a Homozygous Chromosome 4q35.2 Deletion and Hidden IQSEC2 Pathogenic Variant in a Child with Intellectual Disability

Mercan

Clark

Erkal

et al. 2021

Cytogenet Genome Res

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“…In order to establish a genotype-phenotype correlation, the severity of the phenotype is correlated with the size of the deletion. Thus, several reports suggested that small terminal, or interstitial, distal Cr4q del involving bands 4q34 and 4q35 seems to have little clinical impact, consisting in little facial dysmorphism and mild, or absent, intellectual disability (ID) 4 , and Yakut et al 5 reported a case of a familial interstitial 4q35 deletion with no discernible phenotypic effects. On the other hand, a relatively constant phenotype can be recognised in 4q31 to qter deletion.…”

Section: Introductionmentioning

confidence: 99%

Pain insensitivity in a child with a de novo interstitial deletion of the long arm of the chromosome 4: Case report

Cascella

Muzio

2017

Rev. chil. pediatr.

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Introduction. Terminal and interstitial deletions of the distal segment of the long arm of chromosome 4 (Cr4q del) are not common genetic disorders. The severity of the phenotype is correlated with the size of the deletion because small deletions have little clinical impact, whereas large deletions are usually associated with multiple congenital anomalies, postnatal growth failure, and moderate to severe intellectual disability. Alteration in pain tolerance has not been included among these features, also in case of large deletions. The purpose of this report is to document a case of a child affected by interstitial Cr4q del, expressing pain insensitivity as clinical feature not previously described. We also offer a discussion on genetic disorders featuring pain insensitivity/indifference. Case report. A Caucasian girl aged 12 came to our observation for a developmental delay with multiple congenital abnormalities and moderate intellectual disability (IQ 47). A de novo interstitial Cr4 del between band q31.3 and q32.2 (Cr4 del q31.3 to q32.2) was found. The child also expresses no evidence of pain perception to injures which normally evoke pain. Consequently, she is affected by severe disability caused by painless injuries and self-injurious behaviours, such as excessive self-rubbing and scratching. The neurological examination manifested high pain threshold with preserved tactile sensitivity. Conclusions. This is the first report of pain insensitivity in a patient with a specific genetic deletion involving the interstitial region of the distal long arm of Cr4. Moreover, this report could serve as a useful model to better understand mechanisms of pain perception and its modulation.

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“…Alhamoudi et al 2020), vgll4(Czeschik et al 2014)(Barrionuevo et al 2014), and vwa1(Giannikou et al 2012). Among the downregulated genes we also found the following candidates to have such roles; acsl1(Yakut et al 2015), adgb(Alazami et al Miller et al 2009), hoxa13(Fryssira et al 2011), il23r (Rivera-Pedroza et al. 2017, ppp1r42(Mordaunt et al 2015), prodh(Guilmatre et al 2010), six2(Hufnagel et al 2016)(Okello et al 2017), srsf3 (Pillai et al 2019, syt9(Sofos et al 2012), and trpc2 …”

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confidence: 78%

Parallel molecular mechanisms underlie convergent evolution of the exaggerated snout phenotype in East African cichlids

Duenser

Singh

Lecaudey

et al. 2022

Preprint

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Studying instances of convergent evolution of novel phenotypes can shed light on the evolutionary constraints that shape morphological diversity. Cichlid fishes from the East African Great Lakes are a prime model to investigate convergent adaptations. However, most studies on cichlid craniofacial morphologies have primarily considered bony structures, while soft tissue adaptations have been less intensely scrutinised. A rare example of an exaggerated soft tissue phenotype is the formation of a snout flap. This tissue flap develops from the upper lip and has evolved in only one cichlid genus from Lake Malawi and one genus from Lake Tanganyika. To investigate the molecular basis of snout flap convergence, we used mRNA sequencing to compare two species with snout flap (Labeotropheus trewavasae and Ophthalmotilapia nasuta) to their close relatives without snout flaps (Tropheops tropheops and Ophthalmotilapia ventralis) from Lake Tanganyika and Malawi. Our analysis revealed a greater complexity of differential gene expression patterns underlying the snout flap in the younger adaptive radiation of Lake Malawi than in the older Lake Tanganyika radiation. We identified 201 genes that were repeatedly differentially expressed between species with and without the snout flap in both lakes, suggesting that the pathway that gives rise to snout flaps is evolutionarily constrained, even though the flaps play very different functions in each species. The convergently expressed genes are involved in proline and hydroxyproline metabolism, which have been linked to human skin and facial deformities. Additionally, we also found enrichment for transcription factor binding sites upstream of differentially expressed genes such as members of the FOX transcription factor family, especially foxf1 and foxa2, which also showed an increased expression in the flapped snout and are linked to nose morphogenesis in mammals, as well as ap4 (tfap4), a transcription factor showing reduced expression in the flapped snout with an unknown role in the development of craniofacial soft tissues. As genes involved in cichlids snout flap development are associated with many human mid-line facial dysmorphologies, our findings imply a conservation of genes involved in mid-line patterning across vastly distant evolutionary lineages of vertebrates.

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A familial interstitial 4q35 deletion with no discernible clinical effects

Cited by 10 publications

References 20 publications

Coexistence of a Homozygous Chromosome 4q35.2 Deletion and Hidden <b><i>IQSEC2</i></b> Pathogenic Variant in a Child with Intellectual Disability

Coexistence of a Homozygous Chromosome 4q35.2 Deletion and Hidden <b><i>IQSEC2</i></b> Pathogenic Variant in a Child with Intellectual Disability

Pain insensitivity in a child with a de novo interstitial deletion of the long arm of the chromosome 4: Case report

Parallel molecular mechanisms underlie convergent evolution of the exaggerated snout phenotype in East African cichlids

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