Table 2.
Diagnostic Variants in Cases of NIHF.*
| Case No. | Gene | Genetic Disorder | Protein Alteration† | Inheritance | Recurrence Risk percent |
|---|---|---|---|---|---|
| RASopathies | |||||
| H025 | PTPN11 | Noonan syndrome | p.Ala72Pro | De novo (autosomal dominant) | 1–2 |
| H089 | PTPN11 | Noonan syndrome | p.Asn308Asp | De novo (autosomal dominant) | 1–2 |
| H086 | PTPN11 | Noonan syndrome | p.Phe285Ser | De novo (autosomal dominant) | 1–2 |
| H095 | PTPN11 | Noonan syndrome | p.Phe285Ser | De novo (autosomal dominant) | 1–2 |
| H036 | KRAS | Noonan syndrome | p.Thr74Pro | De novo (autosomal dominant) | 1–2 |
| H042 | RIT1 | Noonan syndrome | p.Phe82Leu | De novo (autosomal dominant) | 1–2 |
| H073 | SHOC2 | Noonan-like syndrome with loose anagen hair | p.Met173Ile | De novo (autosomal dominant) | 1–2 |
| H008 | HRAS | Costello syndrome | p.Gly12Ser | De novo (autosomal dominant) | 1–2 |
| H016 | HRAS | Costello syndrome | p.Gly13Arg | De novo (autosomal dominant) | 1–2 |
| H119 | HRAS | Costello syndrome | p.Gly12Asp | De novo (autosomal dominant) | 1–2 |
| H020 | BRAF | Cardiofaciocutaneous syndrome | p.Asn581His | De novo (autosomal dominant) | 1–2 |
| Inborn errors of metabolism | |||||
| H005 | NPC1 | Niemann–Pick disease type C | p.Ile1061Thr, p.Pro691Gln | Maternal and paternal (autosomal recessive) | 25 |
| H019 | GLB1 | GM1 gangliosidosis | p.Gly311Arg, c.75+1delG | Maternal and paternal (autosomal recessive) | 25 |
| H054 | GUSB | Mucopolysaccharidosis type VII | p.Leu12Pro, c.210+1G→A | Maternal and paternal (autosomal recessive) | 25 |
| H068 | GUSB | Mucopolysaccharidosis type VII | Homozygous exon 9 deletion | Maternal and paternal (autosomal recessive) | 25 |
| Musculoskeletal disorders | |||||
| H026 | MYH3 | Multiple pterygium syndrome | p.Ile705Thr | De novo (autosomal dominant) | 1–2 |
| H034 | FGFR3 | Thanatophoric dysplasia type I | p.Arg248Cys | De novo (autosomal dominant) | 1–2 |
| H055 | KLHL40 | Nemaline myopathy | p.Thr506Pro | Maternal and paternal (autosomal recessive) | 25 |
| H085 | SF3B4 | Nager syndrome (also known as acrofacial dysostosis) | p.Met1? | De novo (autosomal dominant) | 1–2 |
| Lymphatic disorders | |||||
| H044 | FOXC2 | Lymphedema distichiasis syndrome | p.Glu343* | Maternal (autosomal dominant) | 50 |
| H050 | FLT4 | Milroy’s disease | p.Arg1041Trp | Paternal (autosomal dominant) | 50 |
| H072 | PIEZO1 | Generalized lymphatic dysplasia | p.Pro1906Lysfs*55, p.Ile2270Thr | Maternal and paternal (autosomal recessive) | 25 |
| Neurodevelopmental disorders | |||||
| H018 | WAC | DeSanto–Shinawi syndrome | p.Ser491fs*9 | De novo (autosomal dominant) | 1–2 |
| H063 | ZEB2 | Mowat–Wilson syndrome | p.Arg695* | De novo (autosomal dominant) | 1–2 |
| H083 | DHCR24 | Desmosterolosis | c.1218+1G→A, p.Gln402* | Maternal and paternal (autosomal recessive) | 25 |
| Cardiovascular disorders | |||||
| H007 | ACAD9 | Mitochondrial complex I deficiency | p.Pro370fs*13, p.Arg266Trp | De novo and maternal (autosomal recessive) | ≤25 |
| H058 | NEXN | Dilated and hypertrophic cardiomy-opathy | p.Arg216*, p.Lys536fs | De novo and maternal‡ | ≤50 |
| H080 | MYRF | Cardiac–urogenital syndrome | p.Ser264fs | De novo (autosomal dominant) | 1–2 |
| Hematologic disorders | |||||
| H027 | RPL11 | Diamond–Blackfan anemia | p.Phe105fs*15 | De novo (autosomal dominant) | 1–2 |
| H094 | PIEZO1 | Dehydrated hereditary stomatocytosis | p.Met870Ile | Suspected maternal mosaic (autosomal dominant) | ≤50 |
| H126 | PIEZO1 | Dehydrated hereditary stomatocytosis | p.Val598Met | De novo (autosomal dominant) | 1–2 |
| Immunologic disorders | |||||
| H056 | STAT3 | Hyper-IgE syndrome, multisystem infantile-onset autoimmune disease | p.Thr341Ile | De novo (autosomal dominant) | 1–2 |
| H113 | FOXP3 | IPEX syndrome | c.543–2→G | Maternal (X-linked recessive) | ≤50 if male fetus |
|
Renal disorder: H107 |
CEP55 | Multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly | p.Arg64*, p.His458Arg | Maternal and paternal (autosomal recessive) | 25 |
|
Ciliopathy: H030 |
DNAH9 | Primary ciliary dyskinesia | p.Arg995fs*5 | Maternal and paternal (autosomal recessive) | 25 |
|
Overgrowth disorder: H109 |
SUZ12 | Imagawa–Matsumoto syndrome | p.Gly484fs | De novo (autosomal dominant) | 1–2 |
|
Other disorder: H124 |
CHD7 | CHARGE syndrome | p.Val1141fs | De novo (autosomal dominant) | 1–2 |
*
CHARGE denotes coloboma of the eye, heart anomaly, atresia of the choanae, retarded growth and development, and genital and ear anomalies; and IPEX immune dysregulation, polyendocrinopathy, enteropathy, X-linked.
†
Coding changes are shown for variants identified in intronic regions.
‡
Two NEXN variants were identified: one of maternal inheritance and the other de novo, for which the cis or trans phase could not be definitively determined on the basis of exome sequencing.