Table 1.
Phenotypic overlap in patients with MGD
| Gene | Zygosity | Alteration(s) pathogenicity | Genetic diagnosis | Indication for testing | |
|---|---|---|---|---|---|
| Completely overlapping | |||||
| 1 | FLG | AD | P | Ichthyosis vulgaris, MIM 146700 | Allergy/Immune/Infections; Derm; Pulmonary |
| SLC27A4 | AR | P/P | Ichthyosis prematurity syndrome, MIM 608649 | ||
| Partially overlapping | |||||
| 4 | DNA2 | AD | P | Progressive external ophthalmoplegia, MIM 615156 | Neuro |
| POLG | AR | P/P | Mitochondrial recessive ataxia syndrome, MIM 607459 | ||
| 5 | HNRNPU | AD | P (dn) | Early infantile epileptic encephalopathy, MIM 617391 | Audiologic; Cardio; Craniofacial; Endocrine; MusSkel; Neuro |
| SMC1A | XLR | VLP | Cornelia de Lange syndrome, MIM 300590 | ||
| 6 | FOXG1 | AD | P (dn) | Rett syndrome, MIM 613454 | GI; Neuro; Pulmonary |
| KAT6B | AD | P (dn) | SBBYSS syndrome, MIM 603736 | ||
| 7a | ETFDH | AR | P (homoz) | Glutaric acidemia, MIM 231680 | MusSkel |
| HEXA | AR | VLP (homoz) | Tay–Sachs disease, MIM 272800 | ||
| 8 | CYP21A2 | AR | P/P | Congenital adrenal hyperplasia, MIM 201910 | Endocrine; Neuro |
| PTEN | AD | VLP | Macrocephaly/autism syndrome, MIM 605309 | ||
| SCN8A | AD | P (dn) | Intellectual developmental disorder, MIM 614306 | ||
| 13 | PTEN | AD | VLP (dn) | Macrocephaly/autism syndrome, MIM 605309 | GI; GU; MusSkel; Neuro |
| ANKRD11 | AD | P | KBG syndrome, MIM 148050 | ||
| 14 | SATB2 | AD | P (dn) | Glass syndrome, MIM 612323 | Cardio; Craniofacial; Neuro; Ophthalmologic |
| CAMTA1 | AD | VLP | Cerebellar ataxia with intellectual disability, MIM 614756 | ||
| 15 | PDE6A | AR | P (homoz) | Retinitis pigmentosa, MIM 613810 | MusSkel; Neuro; Ophthalmalogic |
| SH3TC2 | AR | P (homoz) | Charcot–Marie–Tooth, MIM 601596 | ||
| SLC26A2 | AR | P (homoz) | Multiple epiphyseal dysplasia, MIM 226900 | ||
| 17 | SLC6A1 | AD | P | Myoclonic–atonic epilepsy, MIM 616421 | Neuro; Ophthalmalogic |
| TCF20 | AD | P | Neurodevelopmental abnormalities MIM 603107 | ||
| 21 | PTEN | AD | VLP (dn) | Macrocephaly/autism syndrome, MIM 605309 | Cardio; Craniofacial; MusSkel; Neuro; Pulmonary |
| SON | AD | P (dn) | ZTTK syndrome, MIM 617140 | ||
| 24 | CLTC | AD | P (dn) | Intellectual developmental disorder 56, MIM 617854 | Craniofacial; Hematologic; Metabolic |
| DNMT3A | AD | P (dn) | Tatton–Brown–Rahman syndrome, MIM 615879 | ||
| 26 | NLGN3 | XLR | P | NLGN3 neurodevelopmental disorder, gene MIM 300336 | Craniofacial; Derm; Neuro |
| CAMK2B | AD | VLP (dn) | Intellectual developmental disorder 54, MIM 617799 | ||
| 27 | DNMT3A | AD | P (dn) | Tatton–Brown–Rahman syndrome, MIM 615879 | Craniofacial; Derm; Endocrine; MusSkel; Neuro; Oncologic; Ophthalmalogic |
| ATP1A2 | AD | VLP (dn) | Familial hemiplegic migraine 2, MIM 602481 | ||
| 32 | ARSA | AR | P/P | Metachromatic leukodystrophy, MIM 250100 | Cardio; Craniofacial; GI; Neuro |
| KMT2D | AD | P (dn) | Kabuki syndrome 1, MIM 147920 | ||
| Completely separate | |||||
| 2 | PKD1 | AD | P | Polycystic kidney disease, MIM 173900 | Allergy/Immune/Infections; Derm; GI; Neuro; Ophthalmologic; Renal |
| ANK2 | AD | P (dn) | ANK2 -related autism (no MIM number) | ||
| 3 | ANO3 | AD | VLP (dn) | Dystonia, MIM 615034 | GI; Neuro; Ophthalmologic |
| NALCN | AR | P/P | Hypotonia, psychomotor retardation, MIM 615419 | ||
| 9 | WDR45 | XLD | P (dn) | Neurodegeneration with brain iron accumulation, MIM 300894 | Cardio; Craniofacial; Neuro; Ophthalmologic |
| NOTCH1 | AD | P | Aortic valve disease MIM 109730 | ||
| 10 | ANKRD11 | AD | P (dn) | KBG syndrome, MIM 148050 | Craniofacial; GI; MusSkel; Neuro |
| GAA | AR | P/P | Glycogen storage disease II, MIM 232300 | ||
| 11 | CRB1 | AR | P/P | Retinitis pigmentosa-12, MIM 600105 | Dental; Ophthalmologic |
| WDR72 | AR | P (homoz) | Amelogenesis imperfecta, type IIA3, MIM 613211 | ||
| 12a | DDX11 | AR | P (homoz) | Warsaw breakage syndrome, MIM 613398 | Audiologic; Craniofacial; Hematologic; Derm; MusSkel; Neuro |
| ITK | AR | P (homoz) | Lymphoproliferative syndrome 1, MIM 613011 | ||
| 16 | LRP5 | AR | P/P | Exudative vitreoretinopathy, MIM 601813 | Cardio; GI; Metabolic; MusSkel; Neuro; Renal |
| MT-ND5 | Mito | P | Leigh syndrome, MIM 256000 | ||
| 18 | ATRX | XLR | P | ɑ-thalassemia/intellectual disability syndrome, MIM 301040 | Craniofacial; GI; GU; Neuro, Ophthalmalogic |
| G6PD | XLR | P | Hemolytic anemia, G6PD deficient (favism), MIM 300908 | ||
| 19 | INSL3 | AD | VLP | Cryptorchidism, MIM 219050 | Cardio; Craniofacial; GI; GU; MusSkel; Neuro; Ophthalmalogic |
| ZSWIM6 | AD | P | Frontonasal dysostosis, MIM 603671 | ||
| 20 | ADNP | AD | VLP (dn) | Helsmoortel–van der Aa syndrome, MIM 615873 | Neuro; Renal |
| PKD1 | AD | P | Polycystic kidney disease, MIM 173900 | ||
| 22a | CYP21A2 | AR | P (homoz) | Congenital adrenal hyperplasia, MIM 201910 |
Childhood onset: GU; Endocrine; MusSkel Adult onset: Derm; Endocrine; GI; MusSkel; Neuro; Oncologic; Ophthalmalogic |
| SPAST | AD | VLP | Spastic paraplegia, MIM 182601 | ||
| 23 | PPM1D | AD | P (dn) | Intellectual developmental disorder, MIM 617450 | Audiologic; Craniofacial; Dental; Derm; GI; Metabolic; MusSkel; Neuro |
| WNT10A | AD | P | Tooth agenesis, selective, MIM 150400 | ||
| 25a | GNB5 | AR | P (homoz) | Neurodevelopmental disorder, cardiac arrhythmia, MIM 617173 | Cardio; Pulmonary |
| LRRC6 | AR | P (homoz) | Primary ciliary dyskinesia 19, MIM 614935 | ||
| 28 | PPM1D | AD | VLP (dn) | Intellectual developmental disorder, MIM 617450 | Audiologic; Cardio; Craniofacial; Endocrine; GI; GU; MusSkel; Neuro; Ophthalmalogic; Renal |
| ELN | AD | P | Supravalvar aortic stenosis, MIM 185500 | ||
| 29 | HBB | AR | P/P | Sickle cell anemia, MIM 603903 | Cardio; Craniofacial; Hematologic; MusSkel; Neuro; Ophthalmalogic |
| FOXP1 | AD | P | Intellectual developmental disorder, MIM 613670 | ||
| 30a | CFTR | AR | P/P | Cystic fibrosis, MIM 219700 | Cardio; MusSkel; Neuro; Ophthalmalogic; Pulmonary |
| CNTNAP2 | AR | P (homoz) | CNTNAP2 neurodevelopmental disorder, MIM 610042 | ||
| 31 | CHD7 | AD | P | CHARGE syndrome, MIM 214800 | Derm; MusSkel; Neuro; Ophthalmalogic |
| NF1 | AD | P | Neurofibromatosis type 1, MIM 162200 | ||
| 33a | TYR | AR | P (homoz) | Oculocutaneous albinism type IA, MIM 203100 | Cardio; Craniofacial; Derm; GI; Neuro; Ophthalmalogic |
| VPS13B | AR | P (homoz) | Cohen syndrome, MIM 216550 | ||
For the group of patients with multiple genetic diagnoses (MGD), the phenotypic overlap, or degree that multiple diagnoses could explain the same symptoms in a proband, was scored by exome analysts. Genetic diagnoses that affect only one organ system in that patient at the time of diagnosis are in bold. All indications for testing are childhood onset unless otherwise noted.
AD autosomal dominant, AR autosomal recessive, Derm dermatologic, dn de novo, GI gastrointestinal, GU genitourinary, homoz homozygous, MusSkel musculoskeletal, P pathogenic variant, VLP variant likely pathogenic.
aFamilies who reported consanguinity closer than second cousins.