Chromosome 1q41-Q42 Deletion Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome.

A form of holoprosencephaly (HPE10) has been mapped within the deleted region of chromosome 1q41-q42. For a general phenotypic description and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100).

See also congenital diaphragmatic hernia (DIH; 142340), which has been associated with deletion of chromosome 1q41-q42.

See also Skraban-Deardorff syndrome (SKDEAS; 617616), caused by mutation in the WDR26 gene (617424) on chromosome 1q42, which shows overlapping features with chromosome 1q41-q42 deletion syndrome.

Clinical Features

Shaffer et al. (2007) reported 7 unrelated patients with heterozygous deletion of chromosome 1q41-q42. Common clinical features included significant developmental delay and distinct facial dysmorphism, such as frontal bossing, deep-set eyes, broad nasal tip, depressed nasal bridge, and anteverted nares. Some had coarse facies in infancy, microcephaly, cleft palate, clubfeet, seizures, and short stature. None had frank holoprosencephaly. Two individuals had diaphragmatic hernia and lung hypoplasia with a clinical diagnosis of Fryns syndrome (229850; see, e.g., Van Hove et al., 1995). Shaffer et al. (2007) proposed that the 1q41-q42 deletion syndrome has a variable presentation, with the extreme end of the spectrum demonstrating a Fryns syndrome phenotype.

Kantarci et al. (2010) reported a patient with multiple congenital anomalies, including pulmonary hypoplasia, talipes equinovarus, undescended testes, and dysmorphic facial features, who had a deletion at chromosome 1q41-q41.13 extending from the BPNT1 gene (604053) to the PSEN2 gene (600759). He died at age 1 month.

Wat et al. (2011) reported a Caucasian boy with a de novo 2.2-Mb interstitial deletion of 1q41-q42.12. He had persistent hypoglycemia, failure to thrive, congenital diaphragmatic hernia, delayed psychomotor development, and seizures. Brain imaging showed right hemisphere cerebral volume loss and dilatation of the right lateral ventricle with diffuse thin cortical mantle, atrophy of the right hippocampus, and a thin corpus callosum.

Holoprosencephaly 10

Roessler et al. (2009) reported a girl with seizures, developmental delay, midline cleft lip/palate and mild decortication who was diagnosed as having an HPE sequence with normal CT scan. The authors noted that the apparent absence of brain findings is still consistent with microforms of the holoprosencephaly spectrum. Another unrelated girl had microform HPE, manifest as cleft lip/palate, hypotelorism, upslanting palpebral fissures, and a solitary maxillary incisor.


In a review of the genetics of holoprosencephaly, Roessler and Muenke (1998) referred to a locus on chromosome 1q42-qter as HPE10.


Smith et al. (1994) reported a 9-year-old boy with multiple congenital anomalies, including diaphragmatic hernia, bilateral clinical anophthalmia, and tetralogy of Fallot who had an apparently balanced reciprocal translocation t(1;15)(q41;q21.2).

Slavotinek et al. (2006) identified a de novo interstitial deletion of 1q32.3-q42.2 in a male with congenital diaphragmatic hernia and pulmonary hypoplasia with multiple other congenital anomalies suggestive of Fryns syndrome.

Using array-based comparative genomic hybridization, Shaffer et al. (2007) identified 7 patients with de novo heterozygous microdeletions of chromosome 1q41-q42 that included the DISP1 gene (607502). The patients were identified from more than 10,000 peripheral blood samples from patients referred for evaluation of mental retardation, developmental delay, or dysmorphic features. High resolution analysis of 6 of the 7 cases showed that the deletion sizes ranged from 2.72 Mb to 9.07 Mb, with a minimal shared region of 1.17 Mb (219,486,921 to 220,657,758, NCBI35), containing 5 genes including DISP1. Shaffer et al. (2007) suggested that haploinsufficiency for DISP1 is a reasonable cause for some of the midline developmental defects observed. The deletion breakpoints in the patient reported by Wat et al. (2011) allowed definition of a 2.2-Mb minimal deleted region for congenital diaphragmatic hernia on chromosome 1q41-q42 (223,073,839 to 225,318,623, GRCh37), which contains 15 genes including DISP1, but not including HLX (142995).

Filges et al. (2010) reported a 10-month-old girl with developmental delay, midline defects, and agenesis of the corpus callosum associated with a de novo 5.5-Mb deletion of chromosome 1q42. The girl had mild dysmorphic features, including high anterior hairline, bitemporal narrowing, midface retrusion with depressed and short nasal bridge, enlarged nares, short philtrum, short chin, everted lower lip, cleft palate, persistent ductus arteriosus, clinodactyly, and hypoplastic toenails. She also had rare seizures. Peripheral blood smear showed Pelger-Huet anomaly (PHA; 169400). Array CGH identified the interstitial deletion, of which was 5.3 Mb was in the 1q42.11-q42.13 band and 0.2 Mb was in the 1q41 band. The deletion was predicted to contain about 52 genes, including LBR (600024), which is associated with Pelger-Huet anomaly, as well as genes involved in left-right axis formation (see, e.g., LEFTY1; 603037 and LEFTY2; 601877). However, the 5.5-Mb deletion did not include the DISP1 gene and showed only 0.2-Mb of overlap with the proposed critical region delineated by Shaffer et al. (2007). Filges et al. (2010) suggested that a complex interaction of genes involved in pathways of embryonic development may be responsible for the disorder rather than haploinsufficiency of single genes.

Molecular Genetics

In 2 unrelated girls with microforms of holoprosencephaly, Roessler et al. (2009) identified 2 different heterozygous truncating variants in the DISP1 gene: trp475-to-ter (W475X) and tyr734-to-ter (Y734X), respectively. However, each patient inherited the variant allele from an unaffected mother. In vitro functional expression studies in Drosophila cells indicated that the variants abrogated normal DISP1 function. Roessler et al. (2009) noted that the HPE10 locus is located at chromosome 1q41-q42, and suggested that haploinsufficiency for DISP1 may confer susceptibility to the craniofacial and neurodevelopmental disorders at the mild end of the HPE spectrum, as seen in these girls.