ClinGen Dosage Sensitivity Curation Page

2q13 recurrent region (includes NPHP1)

  • Curation Status: Complete


Location Information

Select assembly: (NC_000002.11) ()
  • Haploinsufficiency score: Gene associated with autosomal recessive phenotype
  • Strength of Evidence (disclaimer): Gene associated with autosomal recessive phenotype

Haploinsufficiency phenotype comments:

Homozygous deletions of this genomic region are associated with nephronophthisis, Joubert syndrome, and Senior-Loken syndrome. A well-characterized phenotype has not been described in association with heterozygous deletions of this region. In a large-scale study (PMID: 21841781) comparing over 15,000 cases referred for clinical array testing due to developmental delay and other anomalies to over 8,000 unaffected adult controls, deletions of this region did not reach statistical significance (P=0.0813). In a study comparing 400 individuals with age-related macular degeneration (AMD) to 500 age-matched AMD-free individuals, heterozygous deletions of this regions were observed 4 times amongst cases and were not observed amongst controls (PMID: 20981449). Another report describes a single 16-year-old male with delayed growth, relative macrocephaly, dysmorphic features, significant developmental delays, hypotonia, and pontine tegmental cap dysplasia on MRI found to have a 96.6-kb deletion at 2q13 (linear location 110,219,766-110,316, 416 bp-hg18) involving NPHP1 (PMID:20434703). Parents were not evaluated at the time of publication, and no other genetic testing results for this individual were discussed.

  • Triplosensitivity score: Triplosensitivity unlikely
  • Strength of Evidence (disclaimer): Triplosensitivity unlikely

Triplosensitivity phenotype comment:

Duplications of this region are commonly found within the control population, with one study finding it in ~1/200 control individuals (PMID: 25217958). A limited number of case reports have also been published on duplications involving this region (summarized below). The patients in these studies have a highly variable clinical presentation, which includes dysmorphic features, developmental delay, and autism spectrum disorder. Parental studies on these patient?s parents have found that the duplication can be inherited from an apparently normal parent as well as de novo. Large scale case control studies have suggested that duplications of this region are enriched in the patient population (248/29,085 Cases versus 92/19,584 Controls p=1.5E-7) (PMID: 25217958). However, recent data from the genome aggregation database (gnomAD SVs v2.1 (non-neuro)) has suggested that there may be ethnic stratification for this duplication (https://gnomad.broadinstitute.org/variant/DUP_2_5708?dataset=gnomad_sv_r2_1_non_neuro), and it is unclear whether the case control studies reporting enrichment have accounted for this. Therefore, it is unclear whether this duplication is truly enriched in the clinical population. Given how common duplications of this region are in the general population, the non-specific clinical presentation that has been reported in association with this duplication, and the fact that has been reported to be inherited from apparently normal individuals, the triplosensitivity score for this region is ?dosage sensitivity unlikely?. Additional information: PMID: 16892302 In Baris et al., (2006) the authors describe 7 patients and one control individual with duplications of NPHP1. Patients with this duplication presented with a highly variable phenotype that included global developmental delay, speech delay, failure to thrive, IUGR, ADHD, craniofacial abnormalities, and other dysmorphic features. Inheritance of the duplication was assessed in 2 of the 7 cases, and in both cases the duplication was inherited from a developmentally normal parent. PMID: 25126106 In Yasuda et al., (2014) the authors examine two patients with de novo duplications of NPHP1. Both patients were diagnosed with autism spectrum disorder, and one of the patients was also found to be schizophrenic. However, neither of the patients were dysmorphic and both were found to have intellectual abilities within the normal range.