Skip to main content

A large Indian family with rearrangement of chromosome 4p16 and 3p26.3 and divergent clinical presentations



The deletion of the chromosome 4p16.3 Wolf-Hirschhorn syndrome critical region (WHSCR-2) typically results in a characteristic facial appearance, varying intellectual disability, stereotypies and prenatal onset of growth retardation, while gains of the same chromosomal region result in a more variable degree of intellectual deficit and dysmorphism. Similarly the phenotype of individuals with terminal deletions of distal chromosome 3p (3p deletion syndrome) varies from mild to severe intellectual deficit, micro- and trigonocephaly, and a distinct facial appearance.

Methods and results

We investigated a large Indian five-generation pedigree with ten affected family members in which chromosomal microarray and fluorescence in situ hybridization analyses disclosed a complex rearrangement involving chromosomal subregions 4p16.1 and 3p26.3 resulting in a 4p16.1 deletion and 3p26.3 microduplication in three individuals, and a 4p16.1 duplication and 3p26.3 microdeletion in seven individuals. A typical clinical presentation of WHS was observed in all three cases with 4p16.1 deletion and 3p26.3 microduplication. Individuals with a 4p16.1 duplication and 3p26.3 microdeletion demonstrated a range of clinical features including typical 3p microdeletion or 4p partial trisomy syndrome to more severe neurodevelopmental delay with distinct dysmorphic features.


We present the largest pedigree with complex t(4p;3p) chromosomal rearrangements and diverse clinical outcomes including Wolf Hirschorn-, 3p deletion-, and 4p duplication syndrome amongst affected individuals.

Peer Review reports


Microscopically visible rearrangements of chromosome 4p16 may result in two separate syndromes: Wolf–Hirschhorn syndrome (WHS) and partial trisomy 4p syndrome. WHS is a well-recognized contiguous gene deletion syndrome associated with prenatal and postnatal growth delay, a typical ‘Greek warrior helmet’ appearance of the nose, microcephaly, and neurological features including seizures, hypotonia and varying degrees of intellectual impairment [1]. In contrast, 4p16 duplication results in partial trisomy 4p syndrome, which gives rise to variable clinical manifestations including intellectual disability, developmental delay and distinctive facial features [24].

About 40–45 % of the WHS cases involve an unbalanced translocation and a deletion of 4p as well as partial trisomy of a different chromosome arm [5]. These unbalanced translocations may be de novo, or inherited from a parent with a balanced chromosomal rearrangement. Different rearrangements of chromosome 4p causing WHS and partial trisomy 4p syndrome in the same family have been reported [24, 6], as have a few reports of isolated unbalanced translocation involving chromosomes 4 and 3 [710]. The size of the chromosomal rearrangement and clinical presentations vary in these cases. Terminal and interstitial deletions of the short arm of chromosome 3 comprises another contiguous gene deletion syndrome (3p deletion syndrome), which may also present with a variable clinical phenotype and associated with a number of different causal deletions. The core features of the syndrome typically include cognitive handicap, growth retardation, microcephaly, and facial dimorphism (ptosis, downslanting palpebral fissures and micrognathia), while variable features include congenital heart defects, postaxial polydactyly, cleft palate, renal and intestinal anomalies [11, 12]. In this report, we document a large Indian pedigree in which individuals have inherited varying combinations of an unusual chromosomal translocation involving chromosome 4p16 and a small section of chromosome 3p26.3, resulting in a range of clinical phenotypes including Wolf–Hirschhorn syndrome, 4p partial trisomy- and 3p deletion syndrome.

Methods and results

Study approval

The present studies were reviewed and approved by the senior investigators from Banaras Hindu University, Varanasi, UP and Medical College, Trivandrum, Kerala and Royal Devon & Exeter NHS Foundation Trust. All tissue samples were taken with informed consent in accordance with all ethical standards and protocols. The ethical clearance number is EC/847 and EC registration No. ECR/526/INSt/UP2014. All subjects or their guardians provided informed consent prior to their participation in the study and for publishing this research article. Written parental consent also was obtained to publish any images of minors. Written informed consent was obtained to publish the photographs of affected individuals.

Clinical report

The family, from Kerala (South India), comprises a total of 36 members over five generations (Fig. 1). All 10 affected subjects were evaluated by a neurologist and a clinical geneticist. Pregnancy and delivery of 9/10 affected individuals was uncomplicated, with delivery at gestational age 38 weeks while IV:11 was born pre-term. Patient clinical data and findings are summarized in Tables 1 and 2.

Fig. 1
figure 1

Left panel: family pedigree including an illustration of the chromosome 3 and 4 al rearrangement detected. Right panel: normal chromosome 3 telomere, demarcated with green circle (a) and normal chromosome 4 telomere, with red circle (b). A balanced translocation outcome is shown in c, while unbalanced translocation outcomes are shown in d (3p duplication and 4p deletion) and e (3p deletion, 4p duplication)

Table 1 Clinical presentation of the three patients with the chromosomes 4p16 deletion and 3p26.3 duplication
Table 2 Clinical presentation of the seven patients with chromosomes 4p16.1 duplication and 3p26.3 microdeletion

V:1 (born in 2000) and V:2 (born in 2004) are the only affected siblings in generation V of the pedigree. Birth weight was 1.5 kg in both cases, length and head circumference at birth were not reported. V:1 was floppy at birth, and developed severe physical and psychomotor developmental delay (sitting at 4 years, currently can only stand with support, delayed or poor eye contact and no speech). A past history of febrile seizures and status epilepticus is reported. Stereotypies of recent onset included rocking and repeated hand washing. Dysmorphic facial features were noted (Table 1; Additional file 1: Figure S1) as well as hand malformations including tapering-long fingers, bilateral inability to abduct the thumb, single transverse palmar crease, hypermobile metacarpophalangeal joints of thumb, overlapping fingers and pes planus. Neurological examination at 12 years of age revealed: increased tone and reflexes in lower limbs. At the age of 12 she developed stereotypic body movements such as bending from side to side, body rocking and hand washing. The younger sibling (V:2) required ventilation for a month post-delivery. Developmental milestones were delayed, walked with support at age 2. Speech is limited to a few words and she is unable to read and write. Generalised tonic-clonic seizures developed at 17 months. Unilateral agenesis of the kidney was seen on ultrasound. Additional clinical features included sacral dimple, overlapping and tapered fingers, flexion contracture of proximal interphalangeal joints, inability to abduct the thumb, simian hand line, hypermobile metocarpophalangeal joint of thumb, rocker bottom feet, prominent talus, medial malleolus, ear deformities (left preauricular sinus, small ears with small lobule, ‘cauliflower’ shaped left ear and pointed pinna). Neurological examination conducted at age 8 revealed left lower motor neuron facial palsy, reduced tone (upper limbs), and increased tone in the lower extremities with exaggerated reflexes. MRI imaging of the brain showed hypo-dense lesions in frontal lobes.

IV:13 is a maternal cousin of siblings V:1 and V:2. His birth weight was 1.8 kg. Developmental concerns were noted early on and progress was similar to V:1. At the age of 2 he had not developed speech and walking, could sit with support and independently roll from back to front. He developed epilepsy with generalized tonic-clonic seizures at 12 months, which is currently under control on phenytoin. He also has swallowing difficulties, drooling and urinary incontinence. He responds to noise, and recognizes his parents. Behavioral problems include self-harm and stereotypies including body rocking movements. Facial features are as described in Table 1 and ear and limb deformities resembling those of V:2. Additional findings included: strabismus, a high arched palate, cleft lip, fixed flexion deformity of the elbows, flat occiput and widely spaced nipples. Neurological examination revealed generalized hypotonia, brisk reflexes and out-turned feet. Ultrasonography revealed kidney malformation, and brain MRI revealed dysgenesis of the corpus callosum.

Individual IV:11 was born pre-term (birth weight 1.2 kg) to consanguineous parents. He had severe developmental delay with no speech and walked with support at age 3. He responds to sounds but hearing function has not been tested. He has a history of surgically treated cleft lip and complex partial seizures. On neurological examination he had gaze evoked nystagmus, limb ataxia, gait ataxia; exaggerated knee and ankle jerks and up-going plantar reflexes. The dysmorphic features are described in Table 2 and Additional file 1: Figure S1. Additional findings on examination were sacral dimple, strabismus and hypospadius. Behavioral abnormalities included stereotypies including rocking, hand wringing, repeated hand washing, head banging and self-harm.

III:4 was the eldest affected child of the third generation. She had no speech or walk until age 2 and has medically resistant secondarily generalized tonic-clonic seizures. At the time of assessment she could not walk unaided, her speech was dysarthric with limited vocabulary and she was unable to read or write. Neurological examination revealed kyphosis, reduced upper limb deep tendon reflexes, absent knee and ankle jerk, hypotonia, scanning speech, gaze evoked nystagmus, and an ataxic gait. Facial features were as described in Table 2. Her daughter, IV:2, started to walk at age 3 and speak at age 4. She displayed aggressive behavior and had mild intellectual impairment. Neurological examination revealed absent knee and ankle jerks and dysarthria. No history of seizures was reported, and distinctive dysmorphic features were noted (Table 2).

IV:17 was born to consanguineous parents. Apart from mild learning difficulties and limited vocabulary, no neurological or other physical abnormalities were detected on examination.

IV:8, IV:9 and IV:1 had delayed walking and speech at 2.5 – 3 years, and similar levels of mild learning difficulties. The birth weight of only IV:8 was documented (2.5 kg). Individual IV:8 could never run due to poor balance, and although he went to a school up to tenth grade, his intellectual abilities are limited. On neurological examination had mild upper and lower motor neuron signs, ataxia and could not stand on his heels. Brain MRI revealed mild cerebral atrophy. Case IV:9 had a previous history of lumbar discectomy. All the observed phenotypic abnormalities are described in Table 2 and Additional file 1: Figure S1.

Microarray analysis and flourescent in situ hybridization (FISH)

DNA samples from family members were genotyped using the Illumina HumanCytoSNP-12 v2.1 microarrays to detect copy-number variations (CNVs). The Illumina Infinium HD assay protocol was followed and the array processed on a BeadStation 500G. Image data was processed in the Illumina GenomeStudio software to generate genotype calls, B allele frequency and logR ratio values. These were further analysed for CNVs using Illumina’s KaryoStudio software. This revealed a 3p26.3 (0–2144867)x3duplication and 4p16.3-16.1 (0–10308871)x1 deletion in three affected individuals (IV:13; V:1; V:2), and a reciprocal 3p26.3 (0–2118422)x1deletion and 4p16.3-16.1 (0–10290552)x3duplication in seven affected individuals (III:4; IV:8; IV:9; IV:2; IV:11; IV:1; IV:17), including two (III:4 and IV:11) with more severe phenotype than others (Additional file 1: Table S1, Figure S1 and Figure S2). For FISH, Kreatech probes D4S33060 and D3S4558 were used to define either balanced or unbalanced t(3p;4p) translocations in three individuals, case V:2, IV:9 and III:3 on whom samples were available for study (Additional file 1: Figure S3).

Discussion and conclusions

We describe a complex reciprocal translocation involving chromosomes 3 and 4 in ten affected family members of a five-generation pedigree, resulting in clinical manifestations of 3 rare chromosomal syndromes. This is, to our knowledge, the first reported case study of a chromosomal imbalance that combines chromosome 4p deletion (WHS), 4p partial trisomy and 3p deletion syndromes in the same family. Nine of the 10 affected family members (II:2; III:7; III:10; III:12; III:14; III:17 and IV:4) were born from a healthy parent with a balanced translocation of chromosomes 3 and 4, while a single affected individual (IV:2) inherited her imbalanced chromosomal complement from her affected mother (III:4) who herself displayed the same 4p16.1 duplication and 3p.26.3 microdeletion.

Deletion of the chromosome 4p region has previously been shown to result in a widely recognized phenotype compared with gains of the same region, which result in more variable clinical manifestations. The family described here includes three family members with chromosome 4p deletion resulting in WHS, all of whom displayed the typical clinical features of this condition. The characteristic phenotype of WHS includes a typical facial appearance, significant intellectual disability and poor growth [13]. The high arched eyebrows and prominent nasal tip that were seen in all three WHS cases described here may relate to the progression of these facial features with age, as has been previously suggested [1]. Similarly, the ear hand and feet anomalies, and dysgenesis of corpus callosum, have previously been documented in WHS cases [1, 14].

At a molecular level, within the terminal 1.9 Mb region on 4p16.3, Wolf-Hirschhorn syndrome candidate region 2 (WHSCR-2) was described as the likely critical region for WHS [15]. Candidate genes in that region have been suggested to cause particular clinical aspects of WHS [16, 17]. Haploinsufficiency of the WHSC1 gene [OMIM 602952], which is disrupted by the proximal breakpoint of WHSCR-2, has been associated with both facial characteristics and growth delay [18, 19]. The LETM1 gene, residing entirely within WHSCR-2, is considered to play an important role in the pathogenesis of seizures [2024]. However, genotype–phenotype correlation analyses suggested that haploinsufficiency of LETM1 alone may not be sufficient in causing seizures and that loss of the terminal 1.5 Mb region with breakpoint at ~300 kb from the LETM1 locus, preserving LETM1, is critical for the development of a seizure disorder [25]. Large deletions of chromosome 4p16 incorporating both critical regions are typically associated with profound intellectual disability, seizures and psychosis in addition to the typical facial appearance [15, 18, 19]. Our microarray analysis of the three WHS cases described here with 4p16.3-16.1 deletion and 3p26.3 duplication identified a ~5 Mb deletion encompassing WHSCR-2 which resulted in severe developmental delay with absent (2/3) or impaired speech (1/3), absent (2/3) or significantly delayed onset of walking (1/3), as well as generalized tonic-clonic seizures (3/3) and behavioral abnormalities (2/3), consistent with those previously described in WHS.

Compared to the classical presentation seen in the three WHS patients, the seven chromosome 4p partial trisomy patients displayed a much more variable clinical picture. The degree of intellectual deficit present across the seven cases varied from severe (2/7) to mild (4/7). The majority of the seven patients displayed clinical features previously described for trisomy of 4p syndrome, including prominent supraorbital ridges (5/7), prominent nasal tip (5/7), prognathism (3/7), camptodactyly (2/7) and malformed and low-set ears (5/7). Although head circumference was reduced in all seven cases, height was variable ranging from normal (5/7) to short stature (2/7) (Table 2). Overexpression or inactivating mutations of two genes mapping to the chromosomal region involved, fibroblast growth factor receptor 3 (FGFR3) and WHSC1, have been reported to be associated with overgrowth features such as macrocephaly, campodactyly and tall stature [26, 27]. FGFR3 is a physiological negative regulator of bone growth, and has been associated with syndromic presentations affecting bone growth including the overgrowth syndrome-CATSHL (campodactyly, tall stature, and hearing loss) [26]. Similarly, overexpression of WHSC1 has been suggested as a contributor to the overgrowth seen as part of this condition. In mice, haploinsufficency of WHSC1 resulted in growth retardation [27]. Two of the 7 chromosome 4p duplication cases (III:4 and IV:11) demonstrated discordant clinical manifestations including severe intellectual disability, short stature, microcephaly, generalized tonic-clonic seizures, gum hypertrophy and cerebellar signs, compared with relatively mild learning difficulties in the remaining five cases (IV:8; IV:9; IV:2; IV:1 and IV:17). The cerebellar signs and gum hypertrophy seen in the 2 severely affected cases may relate to long term phenytoin treatment.

The craniofacial features observed in 1 of the 2 partial 4p trisomy cases (IV:11), including high arched eye brows, hypertelorism, trigonocephaly as well as marked reduction in growth milestones and behavioral changes, are not previously recognized in partial 4p trisomy syndrome (Table 2; & Additional file 1: Figure S1). While this may reflect as-yet unrecognized clinical variability in this disorder, it is more likely to be due to the complexity of the chromosome imbalance in these cases.

The chromosome 3pter rearrangement defined here is somewhat smaller compared with rearrangements previously reported as part of chromosome 3p duplication syndrome. The 2.7 Mb chromosome 3 microdeletion detected in this family includes the CNTN4 and CHL1 genes, which have previously been shown to have a pleotropic effect and contribute to learning difficulties in affected individuals [2833]. Further, CNTN4 deletion has been associated with microcephaly, trigonocephaly, hypertelorism, growth retardation and ear abnormalities. However these clinical features were present in only two of the seven chromosome 3p26.3 microdeletion cases (III:4 & IV:11) presented here. This may mean that other factors including age of examination, other genes in the 3pter region, epigenetic phenomena, expression or regulatory variation and the unmasking of recessive variants residing on the other unperturbed allele, may also be required for the development of these features.

Availability of supporting data

All the supporting data are included as Additional file 1 and available in the online version of the paper.



Wolf–Hirschhorn syndrome


Copy-number variations


Wolf–Hirschhorn syndrome critical regions


Campodactyly, tall stature, and hearing loss


Fibroblast growth factor receptor 3


Leucine zipper/EF-hand-containing transmembrane protein 1


  1. Battaglia A, Carey JC, Viskochil DH, Cederholm P, Opitz JM. Wolf-Hirschhorn syndrome (WHS): a history in pictures. Clin Dysmorphol. 2000;9(1):25–30.

    Article  CAS  PubMed  Google Scholar 

  2. Patel SV, Dagnew H, Parekh AJ, Koenig E, Conte RA, Macera MJ, et al. Clinical manifestations of trisomy 4p syndrome. Eur J Pediatr. 1995;154(6):425–31.

    Article  CAS  PubMed  Google Scholar 

  3. Partington MW, Fagan K, Soubjaki V, Turner G. Translocations involving 4p16.3 in three families: deletion causing the Pitt-Rogers-Danks syndrome and duplication resulting in a new overgrowth syndrome. J Med Genet. 1997;34(9):719–28.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Schonewolf-Greulich B, Ravn K, Hamborg-Petersen B, Brondum-Nielsen K, Tumer Z. Segregation of a 4p16.3 duplication with a characteristic appearance, macrocephaly, speech delay and mild intellectual disability in a 3-generation family. Am J Med Genet A. 2013;161(9):2358–62.

    Article  Google Scholar 

  5. Battaglia A, Carey JC, Wright TJ. Wolf-Hirschhorn (4p-) syndrome. Adv Pediatr. 2001;48:75–113.

    CAS  PubMed  Google Scholar 

  6. Gonzalez CH, Sommer A, Meisner LF, Elejalde BR, Opitz JM. The trisomy 4p syndrome: case report and review. Am J Med Genet. 1977;1(2):137–56.

    Article  CAS  PubMed  Google Scholar 

  7. Schinzel A, Hanson JW, Pagon RA, Hoehn H, Smith DW. Trisomy 3 (p23-pter) resulting from maternal translocation, t (3; 4)(p23; q35). Ann Genet. 1978;21(3):168–71.

    CAS  PubMed  Google Scholar 

  8. Petriczko E, Biczysko-Mokosa A, Bogdanowicz J, Constantinou M, Zdziennicka E, Horodnicka-Jozwa A, et al. Familial distal monosomy 3p26.3-pter with trisomy 4q32.2-qter, presenting with progressive ataxia, intellectual disability, and dysmorphic features. Am J Med Genet A. 2012;158a(6):1442–6.

    Article  PubMed  Google Scholar 

  9. Grossmann V, Muller D, Muller W, Fresser F, Erdel M, Janecke AR, et al. “Essentially” pure trisomy 3q27 -> qter: further delineation of the partial trisomy 3q phenotype. Am J Med Genet A. 2009;149a(11):2522–6.

    Article  CAS  PubMed  Google Scholar 

  10. Han DH, Chang JY, Lee WI, Bae CW. A case of partial trisomy 3p syndrome with rare clinical manifestations. Korean J Pediatr. 2012;55(3):107–10.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Cargile CB, Goh DL, Goodman BK, Chen XN, Korenberg JR, Semenza GL, et al. Molecular cytogenetic characterization of a subtle interstitial del(3)(p25.3p26.2) in a patient with deletion 3p syndrome. Am J Med Genet. 2002;109(2):133–8.

    Article  PubMed  Google Scholar 

  12. Malmgren H, Sahlen S, Wide K, Lundvall M, Blennow E. Distal 3p deletion syndrome: detailed molecular cytogenetic and clinical characterization of three small distal deletions and review. Am J Med Genet A. 2007;143a(18):2143–9.

    Article  CAS  PubMed  Google Scholar 

  13. Zollino M, Murdolo M, Marangi G, Pecile V, Galasso C, Mazzanti L, et al. On the nosology and pathogenesis of Wolf-Hirschhorn syndrome: genotype-phenotype correlation analysis of 80 patients and literature review. Am J Med Genet C: Semin Med Genet. 2008;148C(4):257–69.

    Article  CAS  Google Scholar 

  14. Verbrugge J, Choudhary AK, Ladda R. Tethered cord, corpus callosum abnormalities, and periventricular cysts in Wolf-Hirschhorn syndrome. Report of two cases and review of the literature. Am J Med Genet A. 2009;149A(10):2280–4.

    Article  PubMed  Google Scholar 

  15. Zollino M, Lecce R, Fischetto R, Murdolo M, Faravelli F, Selicorni A, et al. Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet. 2003;72(3):590–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Stec I, Wright TJ, van Ommen GJ, de Boer PA, van Haeringen A, Moorman AF, et al. WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma. Hum Mol Genet. 1998;7(7):1071–82.

    Article  CAS  PubMed  Google Scholar 

  17. Wright TJ, Costa JL, Naranjo C, Francis-West P, Altherr MR. Comparative analysis of a novel gene from the Wolf-Hirschhorn/Pitt-Rogers-Danks syndrome critical region. Genomics. 1999;59(2):203–12.

    Article  CAS  PubMed  Google Scholar 

  18. Wright TJ, Ricke DO, Denison K, Abmayr S, Cotter PD, Hirschhorn K, et al. A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region. Hum Mol Genet. 1997;6(2):317–24.

    Article  CAS  PubMed  Google Scholar 

  19. Rodriguez L, Zollino M, Climent S, Mansilla E, Lopez-Grondona F, Martinez-Fernandez ML, et al. The new Wolf-Hirschhorn syndrome critical region (WHSCR-2): a description of a second case. Am J Med Genet A. 2005;136(2):175–8.

    Article  PubMed  Google Scholar 

  20. Nowikovsky K, Froschauer EM, Zsurka G, Samaj J, Reipert S, Kolisek M, et al. The LETM1/YOL027 gene family encodes a factor of the mitochondrial K+ homeostasis with a potential role in the Wolf-Hirschhorn syndrome. J Biol Chem. 2004;279(29):30307–15.

    Article  CAS  PubMed  Google Scholar 

  21. Schlickum S, Moghekar A, Simpson JC, Steglich C, O’Brien RJ, Winterpacht A, et al. LETM1, a gene deleted in Wolf-Hirschhorn syndrome, encodes an evolutionarily conserved mitochondrial protein. Genomics. 2004;83(2):254–61.

    Article  CAS  PubMed  Google Scholar 

  22. Frazier AE, Taylor RD, Mick DU, Warscheid B, Stoepel N, Meyer HE, et al. Mdm38 interacts with ribosomes and is a component of the mitochondrial protein export machinery. J Cell Biol. 2006;172(4):553–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Jiang D, Zhao L, Clapham DE. Genome-wide RNAi screen identifies Letm1 as a mitochondrial Ca2+/H+ antiporter. Science. 2009;326(5949):144–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. DiMauro S, Kulikova R, Tanji K, Bonilla E, Hirano M. Mitochondrial genes for generalized epilepsies. Adv Neurol. 1999;79:411–9.

    CAS  PubMed  Google Scholar 

  25. Zollino M, Orteschi D, Ruiter M, Pfundt R, Steindl K, Cafiero C, et al. Unusual 4p16.3 deletions suggest an additional chromosome region for the Wolf-Hirschhorn syndrome-associated seizures disorder. Epilepsia. 2014;55(6):849–57.

    Article  CAS  PubMed  Google Scholar 

  26. Toydemir RM, Brassington AE, Bayrak-Toydemir P, Krakowiak PA, Jorde LB, Whitby FG, et al. A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome. Am J Hum Genet. 2006;79(5):935–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Nimura K, Ura K, Shiratori H, Ikawa M, Okabe M, Schwartz RJ, et al. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature. 2009;460(7252):287–91.

    Article  CAS  PubMed  Google Scholar 

  28. Dijkhuizen T, van Essen T, van der Vlies P, Verheij JB, Sikkema-Raddatz B, van der Veen AY, et al. FISH and array-CGH analysis of a complex chromosome 3 aberration suggests that loss of CNTN4 and CRBN contributes to mental retardation in 3pter deletions. Am J Med Genet A. 2006;140(22):2482–7.

    Article  PubMed  Google Scholar 

  29. Conte RA, Pitter JH, Verma RS. Molecular characterization of trisomic segment 3p24.1-> 3pter: a case with review of the literature. Clin Genet. 1995;48(1):49–53.

    Article  CAS  PubMed  Google Scholar 

  30. Kotzot D, Kruger C, Braun-Quentin C. De novo direct duplication 3 (p25-> pter): a previously undescribed chromosomal aberration. Clin Genet. 1996;50(2):96–8.

    Article  CAS  PubMed  Google Scholar 

  31. Pohjola P, de Leeuw N, Penttinen M, Kaariainen H. Terminal 3p deletions in two families--correlation between molecular karyotype and phenotype. Am J Med Genet A. 2010;152A(2):441–6.

    Article  CAS  PubMed  Google Scholar 

  32. Frints SG, Marynen P, Hartmann D, Fryns JP, Steyaert J, Schachner M, et al. CALL interrupted in a patient with non-specific mental retardation: gene dosage-dependent alteration of murine brain development and behavior. Hum Mol Genet. 2003;12(13):1463–74.

    Article  CAS  PubMed  Google Scholar 

  33. Shrimpton AE, Jensen KA, Hoo JJ. Karyotype-phenotype analysis and molecular delineation of a 3p26 deletion/8q24.3 duplication case with a virtually normal phenotype and mild cognitive deficit. Am J Med Genet A. 2006;140(4):388–91.

    Article  PubMed  Google Scholar 

Download references


The work was supported by UK Medical Research Council grants G1002279 and G1001931 and by the Newlife Foundation for disabled children.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Vafa Alakbarzade or Andrew H. Crosby.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

AHC and TI conceived, designed and supervised the project. VA, AS-H, AK and BAC performed experiments. TI and MI aided in family recruitment. TI, VA, CP, ELB, RS, MAP, TMM and TTW aided in assessment of clinical data. VA and AHC wrote the manuscript. All authors read and approved the final version of the manuscript.

Thomas Iype, Vafa Alakbarzade, Mary Iype and Royana Singh contributed equally to this work.

Additional file

Additional file 1:

Supplemental information includes a table that illustrates DNA copy alterations identified using micro-array copy number analysis, the photos of affected individuals, the illustration of beadarray analysis of SNP data, used to identify the chromosomal subregion duplication and deletion events present in family members, and FISH karyotype analyses. (DOCX 1037 kb)

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Iype, T., Alakbarzade, V., Iype, M. et al. A large Indian family with rearrangement of chromosome 4p16 and 3p26.3 and divergent clinical presentations. BMC Med Genet 16, 104 (2015).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:


  • Wolf–Hirschhorn syndrome
  • WHS
  • Complex rearrangement of chromosome 4p16
  • 3p deletion syndrome
  • 4p partial trisomy syndrome
  • Mental Retardation
  • Developmental delay